Salomen Smith Barney on Vasomax
SGP's VASOMAX--NOT DEAD YET, BUT STILL CONTROVERSIAL
Salomon Smith Barney
Thursday, May 06, 1999
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--SUMMARY:--Schering-Plough--Drugs * Investors have written off Zonagen/SGP's VASOMAX for male erectile dysfunction (MED). It is not be dead yet, but it's still controversial. * PFE's VIAGRA is the most effective oral drug for MED with an efficacy response rate of 63-82%, but its interaction with nitrates has created cardiovascular safety concerns--especially among primary care physicians. * In placebo controlled trials, oral VASOMAX efficacy response was 34%-48%. * At the recent AUA meeting, a new long term VASOMAX trial showed an impressive 69% response rate. But the trial was not placebo controlled, so these data are inferior to the 34%-48% from controlled trials. * Regarding nitrate interaction, a study is currently being conducted by SGP to determine if VASOMAX shares this liability with VIAGRA. If it does not, that would be a significant competitive advantage.
OPINION------------------------------------------------------------------- * VASOMAX's liabilities are tachycardia (accelerated heart rate) and hypotension (fainting on standing); the latter could necessitate administering the first dose at the doctor's office which is inconvenient. On April 30, we attended a SGP funded symposium called "Alpha Blockade in Erectile Dysfunction" at the American Urological Association (AUA) annual meeting in Dallas, Texas. At this symposium, some new efficacy and safety data were presented for Zonagen/SGP's oral phentolamine (VASOMAX), an alpha-blocker for male erectile dysfunction (MED). VASOMAX is currently under review at the FDA; the PDUFA (user fee) deadline is July 14, 1999. However, an amendment to the original NDA submission was filed in January 1999, which could extend the user fee deadline.
BACKGROUND Pfizer's oral sildenafil (VIAGRA) is the current gold standard for treating male erectile dysfunction. Viagra's efficacy response rate in placebo-controlled pivotal trials was 63%-82%. PFE launched Viagra in the U.S. in April 1998. After a rapid spike, new prescriptions plunged and stabilized during 2H98 at a much lower level. Unfortunately VIAGRA has a drug-drug interaction with nitrates, which are commonly used to treat heart disease. This gives Viagra an adverse cardiovascular profile with primary care physicians. Zonagen/SGP's VASOMAX could be the second oral drug in the U.S. for MED. The Wall Street perception of VASOMAX: it is a drug with lightweight efficacy (34%-48% response rate in placebo-controlled trials) and significant potential side-effects. This profile is based on results from two pivotal clinical trials that were first reported in May 1997 (press release, conference call), presented at AUA in June 1998, and included in the July 1998 NDA submission. Zonagen initiated two large open label trials (no placebo control) to gain a better understanding of long-term treatment effects with VASOMAX; both are still ongoing,. A summary of the interim results from these trials was presented at AUA on April 30. In one of these open label studies, VASOMAX showed a 69% response rate, much higher than the 34-48% rate demonstrated in the pivotal placebo-controlled trials. Unfortunately, this new trial did NOT contain a placebo control, which makes the 69% response inferior to the 34%-48% in placebo controlled trials. The FDA could allow a mention of the 69% response rate on the VASOMAX label, but it will likely be in a secondary position to the data from the placebo controlled trials. SGP is conducting a drug interaction study with nitrates; these data have not been disclosed. A clean bill of health with nitrates would be a significant safety advantage for VASOMAX versus VIAGRA. But VASOMAX has some unique side effects of its own: tachycardia (accelerated heart beat) and the risk of first-dose hypotension (fainting on standing) that could dictate administering the first dose at the physician's office.
CRITICAL ISSUES 1) In the open label study ZON 303, VASOMAX had a 69% efficacy response rate. Why is this so much higher than the 34-48% efficacy response in the placebo-controlled clinical trials ZON 300 and ZON 301? Will FDA allow SGP to market the 69% efficacy rate since no placebo control was used in this trial? We think these data may be included on the Vasomax label, but in a secondary position to the lower efficacy rates produced in placebo-controlled trials. 2) Patients on nitrates were excluded from VASOMAX trials. SGP is conducting a special drug interaction study, but the results have not been publicly disclosed. Will VASOMAX escape VIAGRA's drug interaction with nitrates and garner this significant competitive advantage? 3) Are the side effects experienced on the 80 mg Vasomax dose (7% incidence of mild to moderate tachycardia plus two cases of blood pressure drops >30%) acceptable for a benign disease like male erectile dysfunction? Will FDA restrict approval to only the 40 mg dose of Vasomax and reject the 80 mg dose? 4) All Vasomax clinical trials required a test dose in the physician's office to identify the small percentage of patients who get orthostatic hypotension (sharp decreases in blood pressure upon standing). Will MD office dosing be required on the Vasomax label, making the drug less user friendly than Viagra? Can this dosing be enforced? 5) Phentolamine was originally introduced in the U.S. in injectable formulation for hypertension by Ciba in 1952. The composition of matter patent on phentolamine has expired. Is Zonagen's phentolamine patent for the treatment of sexual dysfunction via a rapidly dissolving tablet sufficient to keep generics off the market after Waxman Hatch exclusivity expires three years after FDA approval?
VASOMAX EFFICACY LIGHTWEIGHT EFFICACY IN PLACEBO CONTROLLED TRIALS: Based on the two pivotal studies for VASOMAX, most investors concluded that the drug was not very effective for erectile dysfunction. In two small trials of four weeks duration, VASOMAX 40 mg worked in 34%-40% of patients vs a placebo response of 17%-21%. At 80 mg, VASOMAX was effective in 48% of patients vs 17% on placebo. PFE's VIAGRA works in 63%-82% of patients vs placebo 24%. No head-to-head trials of VIAGRA vs. VASOMAX have been performed.
IMPRESSIVE EFFICACY IN NEW OPEN LABEL TRIAL: Zonagen conducted two long term open label trials (NO PLACEBO CONTROL) with VASOMAX. In one of these studies, ZON 303, patients were started on VASOMAX 40mg as needed for one month. Patients not responding to 40 mg were upgraded to 80 mg. Before starting either dose, patients were given an in-office test dose to identify patients who might sustain rapid decreases in blood pressure. Interim data from this study was presented on April 10 at the European Urological Association and on April 30 at the American Urological Association. VASOMAX had a 69% response rate (combined 40 & 80 mg doses) in this trial. In a one-year open label study on PFE's VIAGRA, 88% of patients reported that VIAGRA improved their erections. This data is included on the VIAGRA label and in promotional materials, although in a secondary position to the bar charts from the pivotal placebo-controlled studies showing 63%-82% efficacy response.
VASOMAX SIDE EFFECTS ADVERSE EVENTS: In placebo controlled trials of 4 weeks duration, the primary side effects of VASOMAX were rhinitis, headache, dizziness, and tachycardia. In open label studies, additional side effects not seen in placebo controlled trials were nausea, vomiting, and diarrhea. Source: SGP April 30, 1999 symposium before AUA.
Orthostatic hypotension: Oral phentolamine (VASOMAX) has been shown to sharply reduce blood pressure in some patients after the first dose. Other alpha-blockers -- such as PFE's CARDURA, ABT's HYTRIN, and PFE's MINIPRESS -- also can cause sharp decreases in blood pressure after the first dose. On these drugs, the effect is minimized through a "staged" titration process over several weeks. Unfortunately, VASOMAX is dosed on an "as needed" basis, so titration is not possible. The next best option is a trial dose in the physician's office to identify patients at risk. Side effects on injectable phentolamine: Ciba's iv phentolamine (REGITINE) has been sold in the U.S. since 1952. It is used to treat severe hypertensive episodes. Its label includes a warning that myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following administration, usually in association with marked hypotensive episodes. Other side effects reported on iv phentolamine include acute and prolonged hypotensive episodes, tachycardia, cardiac arrythmias, weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and diarrhea.
DRUG INTERACTIONS Will VASOMAX have a drug interaction with nitrates? SGP is conducting this drug interaction study, but results have not been made public. PFE's VIAGRA cannot be used by patients taking nitrates. No drug interaction with nitrates would be a significant marketing advantage for VASOMAX. Completed drug interaction studies include use with ACE-inhibitors, beta-blockers, calcium channel blockers, and alpha-blockers. Zonagen has also conducted interaction studies in insulin and non-insulin dependent diabetics. Additional special population studies and drug interaction studies are being conducted.
ACCOUNTING SGP licensed the worldwide rights for VASOMAX from Zonagen in November 1997. SGP will book sales and pay an escalating royalty to Zonagen based on sales performance. Zonagen guidance: royalty could reach 20-22% at peak.
FDA REVIEW VASOMAX may not go to an FDA review committee. (Viagra did not have a panel review.) In July 1998, Zonagen submitted the VASOMAX NDA to FDA's Division of Reproductive & Urologic Drug Products Division. This committee is scheduled to meet next on June 3, 1999. VASOMAX will not be reviewed on the date. This is the last scheduled meeting for the committee before the Vasomax user fee deadline of July 14, 1999. However, this data might slip, given the Jan 1998 submission of supplemental data.
PATENT STATUS The composition of matter patent for phentolamine has expired. In March 1998, U.S. patent 5,731,339 issued to Zonagen. This patent covers orally administered rapid dissolving phentolamine having a disintegration time of less than 20 minutes. ERECTILE DYSFUNCTION SALES ($MM) 1997A 1998A 1999E 2000E 2001E 2002E alprostadil (MUSE) $129 $ 39 $ 35 $ 33 $ 30 $ 30 alprostadil (CAVERJECT)$ 88 $ 73 $ 70 $ 70 $ 70 $ 70 sildenafil (VIAGRA) $ -- $788 $1,000 $1,225 $1,425 $1,575 phentolamine (VASOMAX) $ -- $ -- $ 30 $ 60 $ 95 $ 130 apomorphine (UPRIMA) $ -- $ -- -- $ 75 $ 250 $ 375 IC351 $ -- $ -- -- -- -- $ 200 CHRONOLOGY May 1997 First U.S. VASOMAX pivotal trial results June 1997E Open label study ZON 302 started Sept 1997E Open label study ZON 303 started Nov 1997 SGP licenses worldwide rights to VASOMAX Mar 24, 1998 U.S. Patent for rapidly dissolving phentolamine issued May 28, 1998 VASOMAX approved in Mexico July 14, 1998 NDA for VASOMAX submitted to FDA Aug 1998 VASOMAX submitted to UK's MCA Oct 1998 ZON 303 data at LA erection conference Jan 1999 VASOMAX amended filing to FDA Jan 1999 ZON 303 data at small mtg in San Juan, PR April 10, 1999 ZON 303 presented at EUA in Stockholm April 30, 1999 ZON 303 presented at AUA in Dallas July 14, 1999 PDUFA user fee deadline for VASOMAX --- |
