AstraZeneca has unveiled the early efficacy profile of its oral PCSK9 inhibitor in patients with high levels of “bad” cholesterol.
One arm of the Phase 1 trial studied a dose of the drug, dubbed AZD0780, on top of statins in 35 treatment-naive patients with hypercholesterolemia. AstraZeneca’s drug delivered a 52% reduction in the secondary endpoint of change in LDL-C on top of statin treatment, according to results presented at the European Atherosclerosis Society annual meeting Wednesday.
Regina Fritsche-DanielsonThe data were “statistically significant,” according to a company release. “We calculated that if you add 50% [reduction] on top of what statins bring, we would get more than 90% of patients down to their target LDL cholesterol goal,” Regina Fritsche-Danielson, head of R&D at AstraZeneca’s cardiovascular, renal and metabolism unit, told Endpoints News in an interview.
The Phase 1 patients had baseline LDL-C levels of between 100 mg/dL and 190 mg/dL. The optimal level of LDL-C for adults is less than 100 mg/dL.
Overall, the PCSK9-statin combo achieved a 78% total reduction in LDL-C from baseline. The drug was well-tolerated with no serious adverse events, according to Wednesday’s data.
The company’s decision to move the drug into a mid-stage trial in dyslipidemia even before Wednesday’s hypercholesterolemia data reveal “gives you a sense of our excitement” about AZD0780, said Sharon Barr, AstraZeneca’s head of BioPharmaceuticals R&D, at last week’s investor day event.
The 375-participant Phase 2b dyslipidemia trial is “recruiting extremely well” following its initiation in January, Fritsche-Danielson said. The company hopes to have data from this trial toward the end of the year, she added.
Dyslipidemia is an umbrella term that refers to abnormal levels of lipids in the bloodstream and covers a range of separate conditions such as high cholesterol and high triglycerides. Hypercholesterolemia, meanwhile, is specifically about having high cholesterol.
To fast or not to fast
But Merck is ahead in the oral PCSK9 race, having entered Phase 3 development last August.
Sharon BarrIn Merck’s 381-subject Phase 2b trial, the highest dose of its candidate, named MK-0616, lowered cholesterol levels by 61% at eight weeks. The trial recruited participants with baseline LDL-C levels ranging between 70 mg/dL and 250 mg/dL, with a mean baseline level of 119.5 mg/dL. Some patients were already taking statins while others were not.
According to Fritsche-Danielson, Merck’s candidate is not a “true low-molecular weight small molecule” like AZD0780. AstraZeneca’s drug was designed to be absorbed easily and so has the potential for dosing regardless if the patient has eaten or not, she said. Merck declined to respond to an Endpoints request for comment.
In the mid-phase MK-0616 trial, patients were advised to fast for at least eight hours overnight prior to taking the medicine, because food intake can decrease the oral drug’s bioavailability.
According to AstraZeneca, Wednesday’s data showcase their drug’s dosing flexibility with regard to food. That said, food increased total exposure to AZD0780 by around 30% compared to fasting.
Since AZD0780 is a small molecule, it also means AstraZeneca can explore “many opportunities” for fixed-dose combinations, Fritsche-Danielson said. MK-0616 falls under the macrocyclic peptide class that sits somewhere between small molecules and biologics.
AstraZeneca is considering combining AZD0780 with the statin rosuvastatin for high cholesterol as a single tablet to boost compliance, Fritsche-Danielson said. Also, combining the drug with the company’s investigational oral GLP-1, ECC5004, could offer an opportunity in diabetic or obese patients with high cholesterol, she added.
PCSK9 drugs in the market — Novartis’ Leqvio, Regeneron’s Praluent and Amgen’s Repatha — are monoclonal antibodies administered via subcutaneous injection.