Alnylam Pharmaceuticals Inc, a leading RNAi therapeutics company, and The Medicines Company, a global biopharmaceutical company, announced positive initial results from their ongoing phase 1 clinical trial with ALN-PCSsc at ESC Congress 2015 in London.
ALN-PCSsc is an investigational RNAi therapeutic targeting PCSK9 - a genetically validated protein regulator of LDL receptor metabolism - being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies (MAbs) that bind to PCSK9 in blood, ALN-PCSsc is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.
In the phase 1 study, subcutaneous administration of ALN-PCSsc resulted in an up to 83 per cent lowering of LDL-C, with an up to 64 ± 5 per cent mean maximum reduction, comparable to published results for anti-PCSK9 MAbs. Similar reductions in LDL-C were seen in patients on and off concomitant statin therapy. The effects of ALN-PCSsc were highly durable, with clinically significant and clamped reductions in LDL-C maintained for over 140 days, supportive of a once-quarterly and possibly bi-annual subcutaneous dose regimen. Maximal lowering effects on LDL-C were consistently achieved at a dose of 300 mg associated with a low injection volume of 1.5 ml; this dose was significantly below the 800 mg top dose studied per the phase 1 protocol. Importantly, ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events. The development leadership of ALN-PCSsc now transitions from Alnylam to The Medicines Company, who together announced initiation of the Orion development programme, with an initial phase 2 study planned to begin by end-2015 and a phase 3 study expected to begin by end-2017. Orion is also expected to include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs.
"Our initial phase 1 results with ALN-PCSsc, a first-in-class investigational PCSK9 synthesis inhibitor, demonstrate robust, dose-dependent, and durable reductions in LDL-C of up to 83 per cent. Remarkably, significant and clamped lowering of LDL-C is achieved for over 140 days after a single dose. At the 300 mg dose - which we believe is optimal, with fully saturating effects on both LDL-C lowering and PCSK9 knockdown - an injection volume of 1.5 mL and possibly lower can be achieved. Accordingly, we believe that these results support a quarterly, and possibly bi-annual, low volume subcutaneous dose regimen for further development," said Akshay Vaishnaw, M.D., Ph.D., executive vice president of R&D and chief medical officer at Alnylam.
"Importantly, ALN-PCSsc was generally well tolerated with no clinically drug-related significant adverse events to date. Based on these positive results, we believe that ALN-PCSsc potentially represents an innovative, differentiated, and well validated approach for the treatment of hypercholesterolemia. We very much look forward to our continued partnership with The Medicines Company as they now take the lead in developing ALN-PCSsc in the Orion programme."
"Based on these initial phase 1 results, we believe that ALN-PCSsc has a highly competitive profile as compared with anti-PCSK9 monoclonal antibodies that are labeled for twice-monthly dosing. In particular, we believe that a maximally efficacious and well tolerated quarterly or potentially bi-annual, low volume subcutaneous dosing regimen could address the unmet needs for hypercholesterolemia management in a massive, at-risk, often non-adherent population worldwide. Moreover, we imagine that ALN-PCSsc has the potential to open new innovation horizons with patients, providers, and payers by linking the temporal cycle of LDL-C monitoring with administration of therapy," said David Kallend, MBBS, vice president and global medical director at The Medicines Company.
"We are now initiating our broad-based Orion development programme to advance ALN-PCSsc toward approval and the market. We expect to start our initial phase 2 study by end of this year, and plan to start our phase 3 registration studies in 2017. In addition, we plan on performing studies directly comparing ALN-PCSsc with anti-PCSK9 MAbs to confirm the important features and potential benefits of this first-in-class investigational PCSK9 synthesis inhibitor."
"Elevated LDL-C remains a major risk factor for coronary artery disease, and new therapies are needed for patients who are refractory or intolerant to current approaches for management of their LDL-C levels. PCSK9 therapies have now emerged as a new class of drugs for treatment of hypercholesterolemia, and I believe that these agents have the potential to make a meaningful difference for patients," said John J.P. Kastelein, M.D., Ph.D., professor of medicine and chairman of the department of vascular medicine at the Academic Medical Center (AMC) of the University of Amsterdam.
"I am very encouraged by these initial clinical data with ALN-PCSsc, especially the durability of LDL-C lowering effects. If the safety and efficacy of this novel investigational PCSK9 synthesis inhibitor can be confirmed in larger studies to support approval, it may offer an important treatment option for patients, physicians, and payers."
The phase 1 trial of ALN-PCSsc is being conducted in the UK as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. Enrollment in the study has been completed, but the study is ongoing with continued data collection and subject follow up. The study was designed to enroll up to 76 volunteer subjects with elevated baseline LDL-C (= 100 mg/dL), with subjects randomized 3:1, drug: placebo. The study was performed in two phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase. The MD phase also includes subjects both on and off statin co-medication. The primary objective of the phase 1 study is to evaluate the safety and tolerability of ALN-PCSsc. Secondary objectives include assessment of clinical activity as determined by knockdown of plasma PCSK9 levels and lowering of serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc.
All results are based on data in the database as of August 4, 2015. A total of 69 subjects were enrolled in the study, with a mean baseline LDL-C of 146 mg/dL. A total of 24 subjects were enrolled in five SAD cohorts and received placebo (N=6) or study drug at fixed doses from 25 mg to 800 mg (N=3, per group; N=6 for the 800 mg cohort). A total of 45 subjects were enrolled in six MD cohorts, with subjects receiving: placebo (N=12); four doses of 125 mg once weekly (N=6); two doses of 250 mg once every two weeks (N=6); two doses of 300 mg once every four weeks (N=6); two doses of 300 mg once every four weeks with statin co-medication (N=4); two doses of 500 mg once every four weeks (N=6); and two doses of 500 mg once every four weeks with statin co-medication (N=5).
In the SAD cohorts, ALN-PCSsc administration was associated with potent, dose-dependent, and highly durable knockdown of PCSK9 and lowering of LDL-C. An up to 86 per cent maximal knockdown of PCSK9 relative to baseline was achieved, with an up to 82 ± 2 per cent mean maximum PCSK9 knockdown (p < 0.001, compared to placebo). Even in the lowest dose group of 25 mg, significant knockdown of PCSK9 was observed. Maximal effects toward PCSK9 were achieved at the 300 mg dose, with further dose escalation yielding minimal additive effects; the volume of drug at the 300 mg dose was 1.5 ml. Knockdown of PCSK9 was highly durable, with a 62 ± 5 per cent mean effect (p < 0.05, compared to baseline) in the 300 mg cohort maintained at 140 days after a single dose.
In the SAD cohorts, an up to 78 per cent maximal lowering of LDL-C was achieved, with an up to 58 ± 4 per cent mean maximum LDL-C lowering (p < 0.01, compared to placebo); absolute levels of LDL-C as low as 30 mg/dL were observed. As with PCSK9 knockdown, maximal, fully saturating effects on LDL-C lowering were achieved at the 300 mg dose. Reductions in LDL-C were highly durable, with a 44 ± 1 per cent mean lowering (p < 0.001, relative to baseline) in the 300 mg cohort maintained at 140 days after a single dose; data collection beyond 140 days is ongoing. The least squares mean (LSM) per cent reduction in LDL-C from baseline at 12 weeks - a measure used in studies of anti-PCSK9 MAbs - was 50.1 per cent in the 300 mg cohort; this is comparable to the 50-60 per cent range of values reported for MAbs, but was achieved after just a single dose. The durable effects of ALN-PCSsc support a once quarterly, and possibly bi-annual, low volume subcutaneous dose regimen for evaluation in further clinical studies.
In the MD cohorts, ALN-PCSsc was associated with potent and highly durable knockdown of PCSK9 and lowering of LDL-C, with similar effects to those observed at lower study drug exposure in SAD cohorts. An up to 94 per cent PCSK9 knockdown and an up to 83 per cent LDL-C lowering were observed, including absolute levels of LDL-C as low as 18 mg/dL. The LSM per cent reduction in LDL-C from baseline at 12 weeks was 59.4 per cent in the 300 mg once-monthly dose cohort. All MD groups showed similar levels of PCSK9 knockdown and reductions in LDL-C, indicating that all doses achieved a fully saturating effect for a PCSK9 synthesis inhibitor with an approximately 80 per cent knockdown of PCSK9 and an approximately 60 per cent LDL-C lowering. Also, PCSK9 knockdown and LDL-C lowering were similar in subjects with or without statin co-administration, suggesting that ALN-PCSsc may be able to substantially reduce LDL-C in individuals already on a statin and not at target levels. Data collection beyond 98 days is ongoing.
One subject in the placebo group received only a single dose; one subject in the 300 mg qM x2 with statin group received a single dose and discontinued at day 14 due to incarceration; both were excluded
Additional phase 1 clinical activity results - including further durability data for PCSK9 knockdown and LDL-C lowering effects, as well as changes in exploratory biomarkers such as total cholesterol, apoB, non-HDL-C, and Lp(a) - are planned to be presented at a future date.
ALN-PCSsc was found to be generally well tolerated, with no clinically significant drug-related adverse events to date. There were no serious adverse events (SAEs) or drug-related discontinuations. All adverse events (AEs) were mild or moderate in severity. At higher drug exposures of 500 mg or greater, four subjects receiving ALN-PCSsc reported mild, localised injection site reactions (ISRs) that resolved without medical intervention. At or below the lowest maximally effective dose of 300 mg, there were no ISRs noted in any SAD or MD cohort subjects (0/19). One subject in the 500 mg MD group developed alanine transaminase (ALT) elevations approximately 4 times upper limit of normal (ULN) without change in bilirubin, but this was attributed to concomitant statin therapy and improved upon statin discontinuation. There were no clinically significant changes in other laboratory safety measurements, including cytokine levels, or hematologic parameters. There were also no clinically significant changes in renal function tests.
The lead development responsibility for ALN-PCSsc will now transition from Alnylam to The Medicines Company, who together will be advancing ALN-PCSsc in the Orion development programme, a comprehensive global clinical development plan designed to support ALN-PCSsc regulatory approval and market access worldwide. Orion will begin with an initial phase 2 study that is expected to start by end of 2015. Further, the companies expect that phase 3 clinical trials will begin in 2017, and that Orion will include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs.
Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies' agreement formed in early 2013. Under the terms of the agreement, Alnylam will complete certain pre-clinical studies and a phase 1 clinical study of ALN-PCSsc and The Medicines Company is responsible for leading and funding development from phase 2 forward as well as potential commercialisation.
Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the US. Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving adequate LDL-C levels with currently available therapies including statins, including genetic familial hypercholesterolemia (FH) patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies.
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This ESC-GalNAc-conjugate delivery platform is being employed in nearly all of Alnylam's pipeline programs, including ALN-PCSsc and several other programmes in clinical development.
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for physiology or medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.