Amgen Senior VP-Research and Development Joseph Miletich: An Interview With “The Pink Sheet” DAILY (Part 3 of 3)

Miletich discusses the firm’s peptibody candidates in therapeutic areas including autoimmune diseases and oncology.

[Editor's note: Parts one and two of this interview ran in the issues dated ¹ (Also see "Amgen Senior VP-Research and Development Joseph Miletich: An Interview With “The Pink Sheet” DAILY (Part 1 of 3)" - Pink Sheet, 25 May, 2007.) and ² (Also see "Amgen Senior VP-Research and Development Joseph Miletich: An Interview With “The Pink Sheet” DAILY (Part 2 of 3)" - Pink Sheet, 31 May, 2007.).]

"The Pink Sheet" DAILY : Can you talk a bit about your proprietary peptibody platform?

Joe Miletich: It's the Fc part of an immunoglobulin molecule, but then it's fused in the sense that it's all part of the same DNA that's used to engineer the cell, so the cell makes it as a continuous protein. So, it's a fusion in that sense. It's a fusion of the genetic instructions that actually dictate that the molecule be made as a molecule, intact, and then secreted by the cells.

It's a very good platform for us because it allows us to take protein or peptide sequences that might not have adequate pharmaceutical properties on their own - they might be too short lived. Small peptides can often be cleared by the kidneys or other mechanisms very quickly, and they don't circulate for a long enough time, or they might also be susceptible to attack, proteolytic attack by the enzymes that degrade things.

What we've found is that by having these peptide or short protein sequences be expressed as part of this Fc portion, we can still have the specificity and the targeting effects of the short peptide or the protein, but we can actually get the pharmaceutical benefits of something that lasts many days in the circulation and is to some extent protected from degradation. So, it's a very powerful way to extend what we would like to do with peptides and short proteins.

"The Pink Sheet" DAILY: You have Phase III results for your lead peptibody candidate, don't you?

Miletich: Well, our most advanced peptibody is AMG-531. This is our platelet-stimulating compound, so this binds to the thrombopoietin receptor - it's also called the c-Mpl receptor - and it basically stimulates the production of platelets, [which] ...are essential to initiate the blood coagulation process to stop bleeding. This peptibody is an extremely potent agonist peptibody, so it's very low dose.

We've been able to show that in a very interesting autoimmune disease called immune thrombocytopenic purpura, where patients ... develop a syndrome where their immune system basically attacks and destroys the platelets that are made, ...that therapy with this platelet-stimulating agent, AMG-531, can actually increase platelet production to compensate and bring the circulating level of platelets back into the safe zone so that patients aren't at risk for bleeding.

That approach actually defied the conventional wisdom, [which] ...had always been that the immune system was unlimited in its destructive potential, and that you'd never be able to out produce the immune system. ...[Also,] shift the balance back the other way and bring patients back into the safe zone.

We hope to file that for approval for immune thrombocytopenic purpura in the second half of this year in the U.S.

"The Pink Sheet" DAILY: Do you have plans to use peptibody therapies in other indications?

Miletich: We have an early stage compound, AMG-386, that actually neutralizes angiopoietins, substances that are in involved in the signaling that is responsible for generating new blood vessels. Many people know about VEGF, the vascular endothelial growth factor pathway. That's the pathway that many of the kinase inhibitors and that [Genentech's] Avastin [bevacizumab] work against. As a matter of fact, our own [Phase I candidate] AMG-706 works in the VEGF pathway.

Well, the angiopoietins are important in [disabling the ability for tumors to call for blood vessels] as well, and while a lot has been done on the VEGF pathway, we believe there's a lot of promise in the angiopoietin pathway.

AMG-386 is another peptibody that actually neutralizes angiopoietin-2 and to a lesser extent angiopoietin-1, and that pathway, we believe, is very powerful. We've got some very promising Phase I studies, and AMG-386 will move into Phase II studies this year for the treatment of cancers.

"The Pink Sheet" DAILY: What is the lifecycle management plan for your secondary hyperthyroidism therapy Sensipar?

Miletich: Sensipar is ... a small molecule. Not many people understand that Amgen also has expertise in small molecules - not only biologics. Our reasoning for that is that we believe that when we're approaching disease and potential ways to help people, you shouldn't be limited by what kind of molecular modality you make. You should be able to make them all. So, we have a very large chemistry group, and we're very fluent in the language of small molecules as well.

We have a Phase III study going on looking at cardiovascular outcomes, morbidity and mortality, when you treat people who are on dialysis with Sensipar, and secondary hyperparathyroidism. We're looking to see if this really actually has an impact of their cardiovascular outcomes - morbidity and mortality.

If the data show that Sensipar actually improves that ...I think it would become standard of care then across renal dialysis patients. We have approval already for hypercalcemia in patients with parathyroid carcinoma, and then, of course, also for the hyperparathyroidism in end-stage renal disease. The uptake in those indications has been very good.

[Editor's note: In a first-quarter 2007 earnings report, Amgen noted worldwide sales of Sensipar increased 72 percent to $105 million versus $61 million during the first quarter of 2006. The uptake was "principally driven by demand," the firm said.]

"The Pink Sheet" DAILY: Is there anything new and different in the pipeline you'd like to talk about?

Miletich: We do have a number of exciting programs coming forward. I mentioned AMG-386 when we were talking about peptibodies, but we also have some other mechanisms for therapeutics and cancer.

There's a signaling pathway that involves cell death. ...When cells need to be replaced ... that pathway can either be initiated by some internal signaling within the cell, so the cell can sense that it's not working right and can sort of autodestruct by triggering this pathway. Or it can be signaled from the outside, by getting signals to die.

Many tumors actually grow because they've lost that internal sensing mechanism, and ... even though they're not functioning correctly, they've lost the ability to die, to go through apoptosis. Or they've circumvented it in some way. But it is possible to signal from the outside through these other receptors.

We have two programs. One is using a ligand that actually signals through those receptors. That's AMG-951. It's also called Apo2L/TRAIL, and that's a collaboration with Genentech.

We also have AMG-655, which is an agonist monoclonal antibody that signals through that same pathway. Both of these molecules will be entering Phase II studies this year in cancer.

"The Pink Sheet" DAILY: Can you be more specific about the pathway?

Miletich: They signal through receptors. AMG-655 signals through the receptor called the TR-2 receptor, and AMG-951, or Apo2L/TRAIL, signals through two receptors, TR-1 and TR-2. They both have other names as well, but those are the most common names.

There's another program that I'd like to highlight, and that's AMG-785. This is a collaboration with UCB, and this is very interesting because it fits in with the story about denosumab.

I mentioned that there are osteoclasts that are involved in bone resorption, but there are osteoblasts that are involved in building bone. When an osteoblast builds bone, it can actually become embedded in the bone and then become ... an osteocyte, and the osteocyte secretes a protein called sclerostin, which is actually a signal back to the osteoblasts that tells them, "We don't need you to make any more bone."

It turns out, though, that if you inhibit sclerostin, if you neutralize sclerostin or take sclerostin out of the picture, the osteoblasts will continue to build bone.

The ability to potentially be able to influence the positive formation of bone will be very useful, I think, in bone health disorders, and AMG-785 has entered Phase I studies this year.

- Shirley Haley ([email protected])