A Phase 1, Randomized, Single-blind, Placebo-Controlled, Single Ascending Dose, Safety, Tolerability and Pharmacokinetics Study of ALN-PCS02 in Subjects With Elevated LDL-Cholesterol (LDL-C)

The purpose of this study is to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of ALN-PCS02 in subjects with Elevated LDL-Cholesterol (LDL-C).

Start Date01 Sep 2011

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

100 Clinical Results associated with ALN-PCS

100 Translational Medicine associated with ALN-PCS

100 Patents (Medical) associated with ALN-PCS

Literatures (Medical) associated with ALN-PCS

27 Jul 2021·Cureus

Can Clinicians Start Prescribing Inclisiran for Hypercholesterolemia Today? A Review of Clinical Studies for Internal Medicine Physicians and Endocrinologists

Review

Author: Jahangir, Abdullah ; Sahra, Syeda ; Krzyzak, Michael

The safety profile and efficacy margin of inclisiran as a lipid-lowering drug have been assessed in clinical trials and are underway in subgroups with relevant co-morbidities. This systematic review looks at the clinical trials that have been conducted to comment on its safety and efficacy. The conclusions can serve as a guide for practicing physicians and researchers for following current and future cohorts of patients. PubMed, Cochrane, Embase, Scopus, CINAHL, Web of Science, and Clinicaltrials.gov were searched comprehensively using the terms "Inclisiran", "ALN-PCSsc", and "ALN-PCS" using the Boolean operator "OR" with data cut-off date of June 28, 2020. The outcomes of safety and efficacy were collected and charted for the systematic review. In our study, eight clinical trials were included in the final study: the ORION (1,2,7,9-11) trials and two clinical trials (phase 1 randomized clinical trials) done before ORION trials. Favourable efficacy in terms of LDL levels and PSCK9 levels was observed across all eight clinical trials. No severe adverse effects, safety concerns, or fatalities attributable directly to inclisiran were reported. Therefore, our study results suggest a positive efficacy and safety profile of inclisiran as a lipid-lowering drug in clinical trials.

01 Jan 2015·Journal of cardiovascular pharmacology and therapeuticsQ4 · MEDICINE

Looking into the Crystal Ball—Upcoming Drugs for Dyslipidemia

Q4 · MEDICINE

Review

Author: Muthukumar, Rajaram ; George, Melvin ; Elangovan, Shanmugam ; Selvarajan, Sandhiya

Dyslipidaemia is a critical risk factor for the development of cardiovascular complications such as ischemic heart disease and stroke. Although statins are effective anti-dyslipidemic drugs, their usage is fraught with issues such as failure of adequate lipid control in 30% of cases and intolerance in select patients. The limited potential of other alternatives such as fibrates, bile acid sequestrants and niacin has spurred the search for novel drug molecules with better efficacy and safety. CETP inhibitors such as evacetrapib and anacetrapib have shown promise in raising HDL besides LDL lowering property. Microsomal triglyceride transfer protein (MTP) inhibitors such as lomitapide and Apo CIII inhibitors such as mipomersen have recently been approved in Familial Hypercholesterolemia but experience in the non-familial setting is pretty much limited. One of the novel anti-dyslipidemic drugs which is greatly anticipated to make a mark in LDL-C control is the PCSK9 inhibitors. Some of the anti-dyslipidemic drugs which work by PCSK9 inhibition include evolocumab, alirocumab and ALN-PCS. Other approaches that are being given due consideration include farnesoid X receptor modulation and Lp-PLA2 inhibition. While it may not be an easy proposition to dismantle statins from their current position as a cholesterol reducing agent and as a drug to reduce coronary and cerebro-vascular atherosclerosis, our improved understanding of the disease and appropriate harnessing of resources using sound and robust technology could make rapid in-roads in our pursuit of the ideal anti-dyslipidemic drug.

01 Jan 2014·Lancet (London, England)Q1 · MEDICINE

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial

Q1 · MEDICINE

Article

Author: Gollob, Jared A ; Sutherland, Jessica E ; Munisamy, Malathy ; Mant, Timothy ; Shulga-Morskaya, Svetlana ; Liebow, Abigail ; Ritter, James ; Frank-Kamenetsky, Maria ; Fitzgerald, Kevin ; Simon, Amy ; Hutabarat, Renta M ; Chiesa, Joseph ; Nochur, Saraswathy V ; Kotelianski, Victor ; Horton, Jay ; Clausen, Valerie A ; Bettencourt, Brian R ; Vaishnaw, Akshay K ; Karsten, Verena ; Cehelsky, Jeffrey

BACKGROUND:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment.

METHODS:

We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059.

FINDINGS:

Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001).

INTERPRETATION:

Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings.

FUNDING:

Alnylam Pharmaceuticals.

News (Medical) associated with ALN-PCS

17 Mar 2021

·endpts.com

Covid-19 roundup: Alnylam, Vir quietly deprioritize Covid-19 drug; Data suggest AstraZeneca's vaccine is only 10.4% effective against new variant

Vir Biotechnology’s biggest Covid-19 effort has been their monoclonal antibody, a bid they say has since proven effective , but it isn’t their only effort. Last year, the infectious disease biotech signed a deal with Alnylam to co-develop an inhalable siRNA drug that would slice up the viruses inside a patient’s lungs. It would be in the clinic around January, the partners said. That never happened. The calendar turned without word, and at some point in the past few weeks, Vir removed the candidate from their pipeline online. A spokesperson for Alnylam said that they had seen “some evidence of efficacy” in the lab, but not enough to bring it into the clinic. They offered no timeline for starting a trial. “We now have preclinical data showing some evidence of efficacy, however, we plan to collect some additional preclinical data relative to current and emerging therapies,” they said. “We will guide on timelines to an IND at a future date after making more progress with our animal studies.” A spokesperson for Vir said they would continue to develop the drug, but that it was not their main focus. “It is not as front and center the way [monoclonal antibodies] are, but we continue to explore alternative modalities for COVID, including siRNA,” they said. The candidate, called ALN-CoV or Vir-2703, joins a raft of early-stage or clinical efforts, from the pandemic’s early months to face setbacks after initial optimism. Vir has also explored small molecules for Covid-19, although they’ve yet to announce any candidates. Their Covid-19 neutralizing antibody, the centerpiece of their pandemic program, recently failed in hospitalized patients but proved effective in moderate patients, reducing the risk of hospitalization or death by 85%. The siRNA candidate was part of a broader collaboration between the two companies that dates back to Vir’s launch in 2017. That effort is centered on one part of a potential cure for hepatitis B, now in Phase II. — Jason Mast Last month, South Africa halted the rollout of AstraZeneca and Oxford University’s Covid-19 vaccine after a study showed it didn’t protect against mild-to-moderate cases caused by the B.1.351 variant, which is now widespread in the country. Now we’re getting a look at the data. While the vaccine was showing an efficacy of around 75% prior to the spread of B.1.351, a new analysis suggested the vaccine is only 10.4% effective against the variant, according to data published in the New England Journal of Medicine. The study enrolled 2,026 HIV-negative adults, about half of whom were randomized to receive the vaccine. A total of 42 came down with Covid-19, and 39 of those cases were caused by the B.1.351 variant. Overall efficacy in this group, which consisted mostly of cases linked to the variant, was just under 22%. “What this data don’t tell us is whether or not this vaccine might still protect at least against severe Covid-19,” Shabir Madhi, chief investigator of the study, said during a briefing last month. Two days after halting the country’s rollout of AstraZeneca and Oxford University’s Covid-19 vaccine, South Africa’s government said it was considering selling or exchanging the doses it had already received. Work is underway to produce a second-generation version of the AstraZeneca/Oxford vaccine to target new variants, according to a news release. The only serious adverse event to occur was a body temp over 104 degrees Fahrenheit (40 degrees Celsius) after the first dose, according to the researchers. The fever subsided within 24 hours, and all other events were deemed unrelated or unlikely to be related to the vaccine. The news comes as a growing list of countries pause distribution of the vaccine due to reports of blood clots. Austria pulled one batch of the shots last week after a 49-year-old woman died of “severe coagulation disorders,” and another 35-year-old woman suffered a pulmonary embolism. Other countries, including Germany, Italy, Spain, France, Norway, Austria and Thailand, have since followed suit. The EMA is currently reviewing the cases, and said in a statement that there’s currently no indication that the vaccines caused the events. The New York Times reported that the pauses could have more to do with politics than they do with scientific concerns. Nicola Magrini, director general of Italy’s medicines authority AIFA, told the La Repubblica newspaper that the choice to suspend the vaccine was “a political one,” made because other European countries decided to do so, per the Times. For a look at all Endpoints News coronavirus stories, check out our special news channel .

VaccineAntibodySmall molecular drugsiRNA

26 Jan 2021

·www.biospace.com

2021 Biopharma Update on the Novel Coronavirus: January 26

News information is not all-inclusive and updates are published once a week on Tuesdays. Diagnostics A Belgian initiative, icovid, has grown into a multicenter European project. The initiative supports radiologists in the assessment of CT scans of the lungs in COVID-19 patients. Earlier stage detection and the extent of lung lesions can be supported with icolung. Testing Therapies, Antivirals and Vaccines Industry-leading biotech CSL is leveraging its integrated global portfolio to bring urgently needed therapeutic COVID-19 treatments to patients around the world. Read more information here. Moderna reported yesterday that its COVID-19 vaccine offers protection against variants of the virus that are being reported. Last week, Pfizer and BioNTech announced that their COVID-19 vaccine was probably just as effective against the variant strain of the virus, B.1.1.7, found in the U.K. The variant was believed to have emerged in the U.K. in September 2020 and is noted to be more infectious, and possibly more deadly. British scientists suggested last week that the U.K. variant may be approximately 30% more lethal than the most common strain that came out of China. But they’re not completely sure of this yet. Click here for more information. “Children are our future,” goes the oft-repeated refrain, and though the severity of COVID-19 tends to be lower in these cases, the primary vaccine players have shifted at least part of their focus to developing a vaccine for this demographic. With the Pfizer-BioNTech and Moderna COVID-19 vaccines currently authorized in the U.S. and being distributed and dosed, some of the attention is shifting to Johnson & Johnson’s efforts for its one-shot vaccine. Given what has turned out to be a slower-than-expected rollout of the Pfizer-BioNTech and Moderna vaccines, it is hoped that another vaccine, particularly one that probably only requires a single dose, would help mitigate some of the distribution problems. It looks like the J&J Phase III trial of its vaccine may be ready for a data readout in a week or so. The jury is still out on whether Roche’s arthritis drug, Actemra/RoActemra (tocilizumab), is helpful for the most severe cases of COVID-19. Researchers out of Brazil published a small study in the British Medical Journal that did not find the addition of Actemra to standard of care helped the most severe cases. This is a different finding than in several previous trials, including a larger, 800-patient study that found significant benefit. Click here for more information. Organizational Actions/Announcements Merck announced that it is going to stop developing its two COVID-19 vaccine candidates, dubbed V590 and V591, after poor responses in Phase I trials. They are shifting their attention to advancing two therapeutic drugs for COVID-19, MK-4482 and MK-7110. According to Bloomberg, the CEO of Pfizer, Albert Bourla, says the company plans to ramp up the supply of its COVID-19 vaccine and will be able to provide the 200 million doses two months earlier. Other Industry News Excess mortality rates in the U.S. remain high, despite a steady decline since mid-December. The excess deaths are attributed to COVID-19 and its new variants, which have pushed the reported weekly mortality rates well above the pre-pandemic numbers. Click here for more information. A study from researchers at Monash University in Melbourne has identified two molecules in the gut microbiome that can protect against asthma and may possibly reduce the severity of an asthma attack. The study, published in Nature Immunology, found that L-tyrosine, an amino acid commonly sold as a dietary supplement, and gut bacteria byproduct p-cresol sulfate (PCS) has been previously shown to affect asthma outcomes. Additionally, some animal models have suggested they may play a role in treating respiratory illness in severe cases of COVID-19. A year of COVID-19 provides lessons for the future. One year and more than 410,000 deaths later, the United States is still firmly in the grips of the COVID-19 pandemic. Although there are now two authorized vaccines in the United States, newly-inaugurated President Joe Biden has warned that the next few months could be grim ones for the nation. Click here for more information. Americans are still hesitant to be vaccinated against COVID-19, according to just-released research from Invisibly. The online survey of 5,537 Americans conducted between December 4 and 14, 2020 shows Americans nearly equally divided on their willingness to receive COVID-19 vaccines. Only 53% said they were willing to get the vaccine. Despite the rising number of COVID-19 cases reported across the globe, rates of influenza have virtually flatlined across the Northern Hemisphere, leading many doctors and researchers to wonder how this could be replicated in non-pandemic times. Click here for more information.

Vaccine

25 Jan 2021

·www.biospace.com

Gut Bacteria Offer Insight into Molecules Protective Against Asthma and COVID-19

A study from researchers at Monash University in Melbourne has identified two molecules in the gut microbiome that can protect against asthma and may possibly reduce the severity of an asthma attack. The study, published in Nature Immunology, found that L-tyrosine, an amino acid commonly sold as a dietary supplement, and gut bacteria byproduct p-cresol sulfate (PCS) have been previously shown to affect asthma outcomes. Additionally, some animal models have suggested they may play a role in treating respiratory illness in severe cases of COVID-19. In the study, Professor Benjamin Marsland and colleagues sought to understand how the immune system affects the gut microbiome using a mouse model with a limited immune system. The investigators transferred the gut bacteria from this mouse model in mice with a normal functioning immune system to identify which bacteria exerted effects on the overall healthy immune system. The generation of PCS resulted in significant protective effects against allergic airway inflammation, a surprising finding according to the researchers. The PCS in the model was produced via enhanced bacterial metabolism of the amino acid L-tyrosine. In a statement about the researchers, Professor Marsland noted that the metabolite identified in the study “may have a role in other inflammatory diseases,” included COVID-19. Running with this rationale, the investigators tested the metabolites in animals with acute respiratory distress syndrome (ARDS), a risky complication of COVID-19. Similar to the asthma findings, L-tyrosine and PCS was protective against ARDS. The investigators added in their study that they have found the inhalation of PCS directly protects against lung inflammation, indicating that the metabolite may hold potential as an inhaled preventative therapy. Given the safe nature of L-tyrosine and the widespread use of the amino acid in dietary supplements, it’s likely this therapy could be fast-tracked into clinical trials for asthma and COVID-19. "It's very important that a thorough clinical study is performed in order to determine whether L-tyrosine is effective in people with asthma,” said Professor Marsland, “and for us to determine what is the correct dose and treatment regime." In contrast, PCS is suspected to be toxic as it is often unable to clear in many patients with chronic kidney disease. Professor Marsland and colleagues from Monash University have said they have started developing a PCS form that doesn’t feature its potential side effects but may be used as a protective against asthma. The study investigators commented that they will test either PCS or L-tyrosine in a 2021 clinical trial in patients with asthma. The gut microbiome includes the population of bacteria, include probiotic bacteria, that reside in the gut. Research has consistently shown an association with gut bacteria and immune health, with some investigators also showing a connection between the microbiome and cancer, obesity and inflammatory bowel disease. Some studies have even gone as far to suggest that the microbiome influences neurological health, with a preclinical study from the Edinburgh and Dundee reporting last year that a probiotic strain may protect against Parkinson’s disease. As reported in the summer of 2020, the global market for human microbiome products and research is on an exponential growth trajectory. Clinical trials focused on the microbiome have increased to assist in market development, but lack of uncertainty relating to the performance of microbiome-related drugs may impede growth in this field. Most Read Today

100 Deals associated with ALN-PCS

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipoproteinemias	Phase 1	GB	Alnylam Pharmaceuticals, Inc.	01 Sep 2011
Hypercholesterolemia	Phase 1	GB	Alnylam Pharmaceuticals, Inc.	-
Hypercholesterolemia	Phase 1	-	The Medicines Company (Spain) SL	-
Hypercholesterolemia	Phase 1	-	Almac Discovery Ltd.	-

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