Sanofi/Regeneron and Amgen race ahead in PCSK9 inhibitors on positive early data
This article was originally published in Scrip
Interest in inhibiting PCSK9 as a new therapeutic avenue in hypercholesterolaemia is gathering momentum on the back of promising clinical results reported this week showing reductions in LDL-cholesterol of over 70% with two potential drug offerings.
The data come from Sanofi/ Regeneron's REGN727/SAR236553, which has just gone into Phase III, and Amgen's AMG145, which is at the Phase II stage. These are two of the most advanced antibody drug candidates in a range of similar products targeting PCSK9 also in clinical development, including Pfizer's RN-316 and Novartis's LGT-209 (both at Phase II) and others at Phase I (see table).
The new data for REGN727 consist of two Phase II trials presented at this week's American College of Cardiology meeting in Chicago, as well as three Phase I trials published in the New England Journal of Medicine just days earlier on 22 March. Meanwhile, Phase Ib data for AMG145 were also presented at the ACC meeting.
new mechanism
PCSK9 – or proprotein convertase subtilisin/kexin 9 – is a serine protease involved in the metabolism of LDL-cholesterol. PCSK9 is excreted by the liver into the bloodstream where it binds to an epidermal growth factor-like repeat found within the extracellular domain of the hepatic LDL receptor. It is then internalised by the cell, where this binding becomes stronger, preventing the LDL receptor from recycling to the cell surface – it is instead destroyed within the cell. By blocking the action of PCSK9, these drugs should lead to an increase in the number of LDL receptors on the hepatic cell surfaces, and so increased uptake of cholesterol into cells and out of the bloodstream.
As such the drugs have a complementary action to the older statins, which exert their effects by reducing cholesterol production in the liver. This increases the number of LDL receptors in liver cells and increases the uptake of cholesterol from the bloodstream into the liver to compensate. The fact that the new products exert their effects on the LDL receptor could be a key factor in their safety profiles – this approach has already been broadly shown to be safe by the statins.
The PCSK9 inhibitors are being developed for use in patients who cannot meet their treatment goals on statin therapy alone (these drugs can reduce cholesterol levels by 40-55% but this still leaves many patients above the 70mg/dl target) or those who cannot tolerate statins (around 5-10%).
Both companies hope they will also benefit from the trend downwards in target LDL-cholesterol levels. US guidelines for LDL-C levels recently dropped from 80 to 70mg/dl for patients with a very high risk of heart disease. "Many patients are not able to lower their LDL-C sufficiently by diet and medication despite the availability of statins. As guidelines are evolving, there is a real need for additional lipid-lowering medications," said REGN727 investigator Dr James McKenney, president and CEO of National Clinical Research.
"We anticipate with additional studies coming out, the guidelines will drop. We see the evolution of the guidelines and the marketplace continuing to expand for us," added Rob Scott, vice-president of development for Amgen's PCSK9 inhibitor.
Other experts agree that the products could have an important role in therapy for this setting. Writing in an editorial accompanying the publication of SAR346553/REGN727's Phase I trials, Drs Stephen Young and Loren Fong of the University of California say that high-risk patients who have not reached their recommended cholesterol target and patients who cannot tolerate statin "could benefit greatly", but they also note that "patient selection will undoubtedly be influenced by cost-benefit considerations". This in turn could rest on the results of much larger studies looking at clinical outcomes, especially in light of the difficulties faced by Merck & Co's cholesterol absorption inhibitor Zetia (ezetimibe).
Regeneron/Sanofi
The Phase II DFI11565 study of Regeneron/Sanofi's SAR346553/REGN727, which was presented during a late-breaking clinical trials session at the ACC, enrolled 183 patients with elevated LDL-C (>100 mg/dl) despite being on a stable dose of atorvastatin. Across the five different dose regimens tested, patients receiving SAR236553/REGN727 for 12 weeks achieved and sustained a mean LDL-C reduction from baseline of 40% to 72%, when added to existing stating therapy, compared with 5% in patients on placebo (p<0.0001).>
Patients in the study were followed for 20 weeks for safety, and the most common adverse events were injection site reactions. Serious adverse events occurred in one patient receiving placebo and three patients in the active treatment arms, including a patient on active treatment who had the skin rash leukocytoclastic vasculitis. Six patients, all on active treatment, prematurely discontinued therapy due to adverse events. Muscle complaints were infrequent and similar across all treatment groups, and there were no significant elevations in liver enzymes or other lab values in patients receiving SAR236553/REGN727.
The second Phase II study, DFI11566, presented during an oral session, looked at patients with primary hypercholesterolaemia with elevated LDL-C (>100 mg/dl) who were on a stable low dose of atorvastatin (10mg). The primary objective of the study was to compare the effect on LDL-C lowering of switching to a high dose of atorvastatin alone (80 mg) versus a high dose of atorvastatin combined with SAR236553/REGN727. Patients who received SAR236553/REGN727 plus atorvastatin 80mg achieved a mean reduction of 73% in LDL-C, compared with 17% for patients who switched to 80mg of atorvastatin alone (p<0.001) after="" eight="" weeks.="" the="" study="" also="" included="" a="" third="" arm="" in="" which="" sar236553/regn727="" was="" added="" to="" the="" stable="" low="" dose="" of="" atorvastatin,="" and="" patients="" in="" this="" arm="" achieved="" a="" 66%="" reduction="" in="" mean="" ldl-c.="">
After a safety follow-up of 16 weeks the most common adverse event with SAR236553/REGN727 was infection.
A further long-term safety and tolerability study of SAR236553/REGN727 (NCT01507831) is ongoing in patients with hypercholesterolaemia who are not adequately controlled with their current lipid-modifying therapy. Meanwhile, data from three Phase I trials of the product have just been published in the NEJM.
Amgen's AMG-145
Amgen says that on the back of its new data, it is starting a large Phase II programme for AMG-145 that will consist of six studies in a total of 1,900 patients from different populations who cannot be controlled on existing therapies, and the results are expected later this year. Dr Scott said AMG 145 would stand out in the marketplace because Amgen's Phase II clinical trials would evaluate many more patients than Sanofi's and Regeneron's.
The results presented at the ACC were from a Phase Ib study of 51 patients on low-to-moderate stable doses of statins who received AMG-145 every two weeks had mean LDL-cholesterol levels of up to 75% compared with placebo at week six (ie after three sc doses). Patients who received AMG-145 doses every four weeks had up to 66% reduction in LDL-cholesterol at week eight. The magnitude and duration of effect were dose-dependent. For patients on higher doses of statin who received AMG-145 every two weeks had an up to 63% reduction in LDL-cholesterol levels. The most common adverse events were nasopharyngitis and injection site haematoma.
other agents
Both SAR236553/REGN727 and AMG-145 are fully human monoclonal antibodies targeted against the PCSK9 protein, as are most of the anti-PCSK9 products in the pipeline, although Alnylam recently released early clinical data suggesting success using an antisense approach with its candidate ALN-PCS (scripintelligence.com, 5 January 2012). But other approaches to the problem of residual high LDL levels in the statin age are also under investigation.
"Although the discovery of PSCK09 is an exciting chapter in the cholesterol story, no one should assume it is the last," say Drs Young and Fong, as other potential targets are identified, such as IDOL (inducible degrader of the LDL receptor), that also targets LDL receptors for destruction. "As trials of PCSK monoclonal antibodies race ahead in lipid clinics, efforts to identify IDOL inhibitors are probably already under way."
Drug Name | Global Status | Company(ies) | mechanism |
SAR236553/REGN727 | Phase III |
| fully human MAb |
AMG-145 | Phase II |
| fully human MAb |
RN-316 | Phase II | Pfizer | humanised MAb |
LGT-209 | Phase II | Novartis | humanised MAb |
SPC-5001 | Phase I | Santaris Pharma | locked nucleic acid-based inhibitor |
REGN-728 | Phase I | Regeneron | unspecified MAb |
ALN-PCS | Phase I | Alnylam/Tekmira Pharmaceuticals | antisense inhibitor |