RNAi Therapeutics: Liver, CNS and Beyond
Akshay Vaishnaw, M.D., Ph.D.
President, Alnylam Pharmaceuticals
RNAi Could Address Compliance Challenges for Common Diseases
RNAi therapies could boost patient compliance for common diseases by targeting the underlying causes and minimizing the number of doses required, according to Alnylam Pharmaceuticals.
To date, most RNAi-based drugs –double stranded RNA molecules introduced into a cell to suppress the expression of a target gene – have been used for rare diseases. In the future, however, they will be used to treat common disorders, according to Akshay Vaishnaw, M.D., Ph.D., president of Alnylam Pharmaceuticals.
He told delegates at TIDES Europe 2023 that “the company [Alnylam] was started in 2002 with the hope of not just addressing rare disease, but addressing an array of not rare and prevalent disorders.
“Very recently we’re delighted to see the approval of our first RNAi therapeutic targeting, a genetically validated target for a very common disease, namely PCSK9, which is a protease which downregulates the LDL receptor on HEPA hepatocyte surface and increases LDL cholesterol in the peripheral blood.”
According to clinical data, an injection of the therapeutic every six months results in a 50% to 60% reduction in LDL cholesterol relative to placebo.
“There’s a large ongoing program with this drug, which is already approved, to see how this kind of reduction in LDL cholesterol translates to protection from cardiovascular disease, namely heart attacks and strokes. And it’s interesting to see that already in the course of the phase three studies, they started seeing reduction in major adverse cardiovascular events.
“So there’s a 50,000-patient effort going on now to further define the level of cardiovascular benefit associated with this drug that Novartis is undertaking. And the data will emerge in 2026 and 2027,” Vaishnaw said.
Compliance Benefits
Whether lowering LDL cholesterol with RNAi has the therapeutic benefits being sought remains to be seen. But the fact that the product has an impact on LDL levels after a single administration has implications for the wider therapeutic class, according Vaishnaw.
“Perhaps the most important aspect of this drug is that these benefits result from an injection given to patients once every six months. And the reason why that’s important is that whilst there’s the availability of many medicines to lower LDL cholesterol, the problem is patients don’t take their medicines.”
According to Vaishnaw, compliance rates for oral statins fall to around 50% within one year of the drug being prescribed.
“So the idea that we can give a once every six month injection in the doctor’s office and control cholesterol in this way is a very powerful way to think about treating LDL cholesterol in a compliant way to yield the kinds of cardiovascular benefits you’re seeing here,” he said.
There is also potential for RNAi-based hypertension treatments, according to Vaishnaw, and that Alnylam has already seen promising signs from an early phase candidate it is working on.
“To address hypertension, we are selecting another validated target angiotensinogen or AGT … And we give this medicine one once every three or six months to overcome the compliance challenge which we also see in hypertension.
“So the exciting thing is that this work is ongoing now and is in phase two, but the phase one result showed a very clear dose dependent silencing in the target angiotensinogen,” he said, adding “this is a completely new way to treat hypertension.”
Multitarget RNAi Therapies
Another approach Alnylam is looking at for cardiovascular disease is to address multiple targets at the same time using linked RNAi therapies.
Vaishnaw said, “Here the concept is to take two different RNAs that address two distinct targets, one perhaps for LDL cholesterol and the other for hypertension, [then] link them with a linker.”
This “Gemini construct” has already shown promise in primate studies, according to Vaishnaw, adding it “gives rise to a powerful new way to think about treating cardiovascular disease.
“What if you can take two siRNAs, link them like this and give patients an injection once every six or 12 months? Effectively, you’ve generated a kind of immunization against cardiovascular disease.”
