The above study was done way after the AdCom (actually in Jan 2014)
I am a calm guy. Never "ALL IN". And I employ trading Options. There are always "bottoms" and "peaks," and I never put my chances into one basket.
Anyway, appreciate your concerns -- hopefully, you can make some real money than just bashing with empty hands.
The primary endpoint of REDUCE-IT (RI) is MACE (major adverse cardiac event, including heart attack, stroke, cardiovascular surgery, hospitalized angina). In OCT 2013, FDA’s estimate of MACE rate in RI population was 5.2%. The rate should go up gradually in patients with placebo (due to high-triglyceride progressing) and go down gradually in patients with Vascepa 4g/d (due to treatment effect proven by ANCHOR). The RI protocol requires the size of 8,000 patients with high triglyceride. MACE cases target 1,726 to distinct placebo from treatment by statistical significance, and an interim analysis will happen as MACE reached 976 cases.
Counting on the size of 6,400, the annual total MACE cases is expected to be 333, based on 5.2% rate. RI started in Nov 2011, and the size gradually reached 6,400 in Dec 2013. Assuming, conservatively, there were 350 cases MACE occurred in RI prior to the end of 2013, thus there will be 683 MACE cases accumulated at the end of 2014, and 1,016 accumulated cases at the end of 2015. Therefore, an interim analysis of RI would be occurring in late 2015.
However, deaths may change the timetable. In ANCHOR Study (702 patients in total), there were four CVE in two patients (including one death caused by MI) with placebo, one CVE with Vascepa 2 g/d, and 0 CVE with Vascepa 4 g/d, in a 12 Week timeframe. Converting to annual death rate, it was 0.6% (a point estimate, not reliable). Whenever, death number can distinct the two arms (placebo and Vascepa) with statistical significance, FDA will terminate RI and announce the conclusion.
Since many new comers here. It is worth to pick up some old researches in this board to show people how deep we have been reached. In this post, I would like to use ACHOR data to show the dynamics of a successive REDUCE-IT.
Serum Triglyceride vs Time, ANCHOR Study
Screening (6W)_|_Randomized Treatment (12 Weeks)
* Serum Triglyceride Level with Placebo (N = 227)
# Serum Triglyceride Level with Vascepa 4 g/d (N = 226)
| vertical bar division of screening phase and treatment phase
All ANCHOR patients are statins takers. The placebo data demonstrated that high triglycerides keep progressing, about 100 mg/dL increment per year averagely, beyond statins’ control. Vascepa 4 g/d data demonstrated a rapid reduction of triglyceride, about 20% averagely, in the first four weeks, then triglyceride keep gradually declining thereafter.
REDUCED-IT and ANCHOR are in the same population
The placebo data of ANCHOR Study revealed that triglyceride keep elevating, about 100 mg/dL per year in a linear pace averagely, in patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). The patients supposed to be in REDUCE-IT for 4-6 years. Therefore, triglyceride in most patients with placebo in REDUCE-IT will shoot up above 500 mg/dL. Even though “FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL” (I believe that FDA will change their tune soon), they already recognized that serum triglyceride greater than 500 mg/dL causing greater cardiovascular risks. Therefore, no doubt MACE (major cardiac event) keep elevating in REDUCE-IT patients with placebo.
BTW, in ANCHOR (702 patients in total), there were four CVE in two patients (including one death caused by MI) with placebo, one CVE with Vascepa 2 g/d, and 0 CVE with Vascepa 4 g/d, in a 12 Week timeframe.
Right now, RED CHTP is down below its critical level: below $5. As pps below $5, forget BUYOUT, forget PARTNER, even forget Secondary. Ugly, ugly, ugly.
Allow me do a serious one:
Originally, financials estimate Northera could realize $450M in 2018. However, the restrictions with the conditional approval changes that. Lacking of durable effect plus Black-Boxed Warnings means that doctors won't prescript Northera with long-term refills -- two weeks a time will fit the data well (remember black-boxed "strokerisks", it could be very costly to doctors) . This one alone will cut the $450M into a half. Another factor is the 6y P-IV Study in 1,400 patients for durable effect. It is a stone hanging on the company's neck. It is the major factor discouraging suitors to put a reasonable bet on the table (rather wait for a preliminary outcome). If the original target price is $12, the it should become $6. The treading pps would be $6 originally, now $3 is possible. If the company fail to right its direction, the pps could stay aroung low single-digit for a long time till the preliminary outcome come out.
CHTP "longs" need to do better DD.
Buyout/Partner? Significant weaknesses of the product, of the company and of the management don't support a Buyout/Partner at all.
Midodrine "yield" the road to Northera? Shire has withdrawn the midodrine NDA. But they won't report midodrine trials results (their most important trial will finish at the end of 2015) to the public. And the generics midodrine still listed in the Orange Book! Someone tried to use the logic of "No NDA, no generic." In fact, there was an NDA, and there were generics. NDA was withdrawn by the owner, but the generics owners didn't withdraw their ANDA. The best way is to follow the Orange Book. If the midodrine generics are still listed on the Orange Book, they are still legally in the market. Unfortunately, many CHTP longs even don't know how to access the Orange Book.
Seemingly, CHTP longs are living in their dreams.
Unfortunately, Shire has already announced they won't publicize the trial results, even the results will be ready at the end of 2015.
For CHTP longs, doing DD is the must. You can only make right decision when you occupied enough information and correctly analyzed.
About 20% of adults faint recurrently. These patients are often highly symptomatic, have problems with employment and driving and have reduced quality of life. There are no therapies that have withstood the test of adequately designed and conducted randomized clinical trials. Midodrine is a prodrug whose metabolite is an alpha-1 adrenergic agonist that increases venous return to the heart and raises blood pressure. There is considerable lower level evidence that it might prevent vasovagal syncope.
The investigators will test the hypothesis that Midodrine prevents recurrences of syncope in patients with moderate to severe vasovagal syncope.
Drug: midodrine hydrochloride
Drug: matching placebo
Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Assessment of Midodrine in the Prevention of Vasovagal Syncope: The Prevention of Syncope Trial IV (Post 4)
Resource links provided by NLM:
MedlinePlus related topics: Fainting
Drug Information available for: Midodrine hydrochloride
U.S. FDA Resources
Further study details as provided by University of Calgary:
Primary Outcome Measures: •The primary outcome measure will be the proportion of patients having at least one syncope recurrence. [ Time Frame: 1 year. ] [ Designated as safety issue: No ]
Secondary Outcome Measures: •A secondary outcome will be the time between the first and second syncope recurrences. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
•A secondary outcome will be the frequency of syncopal spells. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
•A secondary outcome is the number, duration, and severity of presyncopal spells (as measured with the Calgary Presyncope Scale(19)). [ Time Frame: 1 year. ] [ Designated as safety issue: No ]
•A secondary outcomes will be quality of life as measured by the EQ-5D and the ISQL. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Estimated Enrollment: 108
Study Start Date: November 2011
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Do you know Orange Book? Do you know how to excess Orang Book (I guess you don't). Take a look for yourself. All generics by Apotex, IPXL, Sandoz, Mylan and Upsher are listed there.
Shire won't say anything about Midodrine Trials except withdraw the NDA, just as CHTP keep deep silence.
BTW, please visit Orange Book: all generics are still listed in Orange Book, i.e., in the market as Shire keeps silence as CHTP does.
Suppose the underwriter is also a Market Maker, the positions gives more degree of freedoms to the MM. Recently, a few couple of Reversal Trading have been exercised (up in a down day, and down in an up day).
Up in a down day will induce weak-hands sell out with confusion. At the following up down-day, those weak-hands confused again and couldn't making any money in those reversal tradings.
Starting its own marketing?
The company only have less than $40M cash now. It is definitely not enough.
Secondary? How much the underwriter is willing to issue. With product's significant weaknesses and company's deep silence, I doubt the company can do another $20M. The most important is "no debts". Once the company involves debts, bankrupt is waiting there.
Seemingly, there is some support from someone while PPS going lower low. Who is it? Perhaps, the underwriter of the secondary? Unfortunately, coming secondary will have a price around $4. Even though, the company should get the secondary ASAP -- PPS heading south.
Analysts said 10% WoW is OK. It didn't happen.
Then they said 7% WoW is OK. Neither did.
Recently, they OKed 5% WoW. Still not in sight.
Now is "TV Ads." We will see. What is else? A marginal effective weight-losing drug with side-effects -- don't expect too much.
Judging a company with approved product, 3 aspects are critical:
1) Marketability (Patient Population, Treatment Efficiency, Pricing)
2) Protectability (Patents and Exclusives)
3) Financing Position (Cash, Debt, ....)
Northera has very good exclusives (ODE and NCE). Unfortunately, no too much left except that.
Patient Population is small.
Treatment efficiency has some significant deficits, particularly lacking of durability (imagining that the patient has to stop the treatment after two week on the treatment, how can the company make money from that). Buyout or Partner is limited by that.
The company has only $40M cash now. The first year of commercialization needs $100M, and the Study needs about $15M per year for next 6 years.
For sure, the company is preferring B or P. The problem is valuation. With lacking of durable effect and limiting by costly long-term Study, the current valuation is no good. The deep silence means that the tiny company don't know what to do.