“These data present challenges to our programme,” could be one of the biggest understatements of the year, uttered by Affymax’s chief medical officer, Anne-Marie Duliege, on a conference call today to discuss phase III results from the company’s only pipeline candidate, the erythropoietin-stimulating agent (ESA) Hematide.
Although overall efficacy and safety data from four trials was positive, a worrying and perhaps terminal cardiovascular risk signal was seen in non-dialysis patients, with greater rates of death, unstable angina and arrhythmia observed in the Hematide group. Investors were understandably spooked, sending Affymax shares crashing 64% in early trade to $8.35, a record low since the company went public at the end of 2006. This decline re-values the Californian company at $200m, just above its first quarter cash position of $168m, suggesting Hematide’s chances of breaking into the lucrative but challenging ESA market are slim to zero.
Wrong side of binary
Phase III data from four trials, two in dialysis patients (Emerald 1 & 2) and two in non-dialysis patients (Pearl 1 & 2) with anaemia from chronic renal failure, was always going to be a massive binary event for Affymax, whatever the outcome (Event - Expectations high for Hematide phase III data, but bundled payments await, February 17, 2010).
Positive results with minimal or manageable safety issues could easily have generated share price gains as dramatic as the losses hurting the company and its shareholders today.
Regarded as potentially a safer and more conveniently dosed ESA to current incumbents such as Amgen’s Epogen and Aranesp, analysts had placed a $1bn peak sales label on Hematide, with Affymax’s partner Takeda expected to generate $735m in product revenues by 2016.
With Affymax to receive half of US revenues and royalties elsewhere, Hematide was potentially worth $1.49bn to the company, according to EvaluatePharma’s NPV Analyzer.
Seriously adverse events
The four trials were all designed to prove non-inferiority of Hematide against Epogen in dialysis patients and Aranesp in non-dialysis patients.
In terms of improving or maintaining haemoglobin levels within an acceptable target range, Hematide was non-inferior across all the studies. In terms of pooled safety data for all four trials there was no significant difference in cardiovascular composite safety endpoints (CSE), which include death, stroke, myocardial infarction, congestive heart failure, unstable angina, and arrhythmia.
Further, in the dialysis (Emerald) trials, there was also no significant difference in CSEs between Hematide and Epogen.
However, the devil is always in the detail and what could pull the plug on Hematide completely was a significant increase in CSEs for the experimental drug in the non-dialysis (Pearl) setting, when compared to Aranesp.
In addition, Ms Duliege revealed on the conference call today that major differences were seen in terms of rates of death, unstable angina and arrhythmia; full details are below.
|PEARL studies - % of patients reporting serious adverse events|
|SAE||Hematide group||Aranesp group|
|Unstable angina *||2.4%||0.9%|
|Congestive heart failure||8.7%||8.6%|
|* signifcant difference between Hematide and Aranesp groups|
Another alarming statistic quoted by Ms Duliege was that of the main differences observed in death rates between Hematide and Aranesp, the main cause was sudden or unknown primary cause of death.
Next painful steps
Naturally Affymax was keen to emphasise that the full data set still needs to be analysed further although the company admitted it was at a loss to explain the results or why there should be a marked difference in safety between dialysis and non-dialysis patients.
In general terms the dialysis market is much larger, representing $3bn of the $4bn ESA market in the US for patients with chronic kidney disease, according to analysts at RBC Capital Markets.
As such, there is a chance Affymax could seek to gain approval for Hematide in the dialysis setting only, but that remains a slim chance given the nature of the cardiovascular safety signal in non-dialysis patients.
The FDA has already adopted an increasingly tough stance on the safety of ESAs, indeed Merck’s recent ditching of its follow-on ESA biologic following the FDA’s request for extensive cardiovascular outcome data is an indicative of this (Merck's ditching of Aranesp biosimilar highlights FOB pitfalls, May 14, 2010).
Hemtatide always had to show a super clean bill of health if it was to stand any chance of regulatory or commercial success, unfortunately today it does not look whiter than white. Affymax will be undergoing much soul searching over the coming months.