ACC PREVIEW: What drug trials will be hot in Washington DC?
This article was originally published in Scrip
Amgen's investigational PCSK9 inhibitor evolocumab is set to dominate pharma trials at this year's American College of Cardiology meeting, as the first major tranche of Phase III data for this high-profile new drug class get a proper airing at the meeting in Washington DC on 29-31 March.
Amgen has already announced positive top-line results from six of its Phase III trials for evolocumab, but this will be the first detailed look at the data from five of them, and following the FDA's recent decision to probe the PCSK9 inhibitors for adverse neurocognitive events, attention will inevitably focus on the side-effect profiles. The FDA's interest has dented sentiment surrounding the entire class, knocking shares in their developers, although it is expected that any signal is likely to be small and not result in any material delay to the products' timelines (scripintelligence.com, 8 March 2014).
"It will be important to see if anything comes out at the conference that triggered the FDA's concern, as well as any data on cognitive side-effects from evolocumab's program," says BioMedTracker analyst Dr Peter Chang. He noted that there was some imbalance for memory loss in the Phase II OSLER study, but Amgen has so far denied any neurocognitive signal in their program.
Two of the studies will be featured in the first Late-Breaking Clinical Trials session on Sunday 30 March: the LAPLACE-2 study comparing evolocumab with placebo and ezetimibe in combination with statin therapy in patients with primary hypercholesterolemia and mixed dyslipidemia; and the GAUSS-2 study in looking at evolocumab in hypercholesterolemic patients unable to tolerate statin therapy (scripintelligence.com, 23 January 2014).
Three more trials – MENDEL-2, DESCARTES and RUTHERFORD-2 – will form the basis of the Featured Clinical Research session a day earlier on 29 March. Last week, Amgen released positive top-line data from a sixth Phase III trial, TESLA, in homozygous familial hypercholesterolemia, which will be presented in full at another future conference. In total, Amgen's PROFICIO Phase III program for evolocumab includes 14 studies. The company has yet to confirm when it will file for approval of the product.
So far, all Amgen has said is that the results are consistent with the Phase II findings, heightening interest in the precise Phase III data points, in particular with respect to the effect of different dosing schedules as delivery profiles look set to be a major differentiator in this novel drug class. Only some of the Phase II studies used a dosing schedule of every two weeks, and the once-monthly dosing Phase II study showed large swings in LDL-cholesterol levels that were not as strong at the endpoint as those seen with the fortnightly dosing. The Phase III data should help show how competitive the monthly dosing efficacy profile will actually be, said Dr Chang. Nearest competitor Regeneron/ Sanofi's alirocumab will be administered using a 1ml autoinjector for its every other week dosing. Amgen has yet to disclose the injection volume for evolocumab, although Dr Chang says it seems likely that its every other week dose will likewise be delivered using an autoinjector.
For its part, alirocumab will have a lower profile at the ACC, with only poster presentations scheduled, six on 30 March, though it will present monthly dosing data from an early stage study. The main body of its Phase III data is not due until mid-year (with likely presentation at the European Society of Cardiology meeting in September, or the American Heart Association meeting in November), delaying a comprehensive comparison of the two products' profiles.
Earlier-stage rivals are also making a small appearance each, with poster presentations for Pfizer's bococizumab (Phase IIb subcutaneous) and Bristol-Myers Squibb's BMS-962476 (the first clinical data) scheduled, again, on 30 March. Other companies are also developing similar products (see table below):
| Drug name
| Company
| Development Phase
|
| Evolocumab (AMG-145)
| Amgen
| Phase III
|
| alirocumab
| Regeneron/Sanofi
| Phase III
|
| bococizumab
| Pfizer/Halozyme
| Phase III
|
| LY-3015014
| Eli Lilly
| Phase II
|
| RG-7652
| Roche
| Phase II
|
| BMS-962476
| Bristol-Myers Squibb
| Phase I
|
| K-312
| Kowa
| Phase I
|
| ALN-PCS
| Alnylam/ Tekmira / The Medicines Company
| Phase I
|
At a press preview ahead of the meeting, the conference's program co-chair Dr Prediman Shah of the Cedars-Sinai Medical Center in Los Angeles said that he believed long-term outcomes studies were needed to "decide whether these [drugs] will be really a major addition or something more incremental". As yet there are no long-term data on off-target side-effects, he noted, referring to the FDA's request to look at neurological function. It is "unclear why the FDA is requiring this information to be tracked. Maybe they know something we don't… It will be very interesting to hear the results being presented," he said.
lessons from failures
Meanwhile, academic interest will be taken in the full data presentations also in the 30 March Late-Breaking session of two high-profile Phase III study failures initially reported last year: for GlaxoSmithKline's darapladib and Roche's aleglitazar.
Roche dropped aleglitazar in July after a failed Phase III trial looking at its effect in reducing cardiovascular risk in type 2 diabetics failed on safety and efficacy grounds, effectively sounding the death knell for dual PPAR inhibition as a strategy for Big Pharma following previous disappointments with Bristol-Myers Squibb's Pargluva (muraglitazar) and AstraZeneca's Galida (tesaglitazar) in 2006, despite local success in India with Zydus Cadila's Lipaglyn (saroglitazar) (scripintelligence.com, 10 July 2013).
There is life still in GlaxoSmithKline's LpPLA2 inhibitor darapladib though, with an ongoing study in acute coronary syndromes (ACS), but the blockbuster hope crashed in the Phase III STABILITY trial in November, failing to reduce the cardiovascular events in patients with coronary heart disease (scripintelligence.com, 12 November 2013). Here the chief interest will be in whether the researchers have any reason to believe the product will have more successful in ACS. Darapladib became the leading drug in this new class following the failure of Anthera Pharmaceuticals' varespladib in 2012, but with the exception of GSK's rilapladib in Phase II, all other candidates in this class are under investigation by small companies. STABILITY will also be the subject of a Deep-Dive Late-Breaking Clinical Trials session on Monday 31 March.
future of resistant hypertension
Pharma companies may also be interested in the full data from the SYMPLICITY HTN-3 study of Medtronic's Symplicity denervation device technology for treating resistant hypertension. Although this product is already on the market in Europe and had shown great promise in earlier studies, this trial failed to meet its primary endpoint of blood pressure reduction at six months.
"Since this was conducted in a more rigorous way than past positive trials is there any hope for a different trial or other devices? If not, the failure could eliminate competition from such devices for pharmacologic approaches to resistant hypertension," said Dr Chang. The study will be highlighted at the opening Late-Breaking Clinical Trials session on the Saturday 29 March.
other controversies
Other sessions at the ACC will look at ongoing controversial issues, including the value of HDL cholesterol as a target and looking at the emerging landscape for HDL therapeutics, and the use of niacin/fibrates (on 29 March).