Simultaneous antagonism of both the renin-angiotensin system (primarily mediated by angiotensin II via AT1 receptors) and the endothelin system (primarily mediated by endothelin-1 via ETa receptors) can produce a greater reduction in BP and added CV benefits than antagonism of either system alone.
PS433540 is a first-in-class, potent, orally active, dual-acting angiotensin AT1 AND endothelin ETa receptor antagonist (DARA). These highly selective, dual antagonist actions of PS433540 may offer significant improvement in efficacy compared with ARB (Angiotensin Receptor Blocker) monotherapy for HTN and related CV diseases. The purpose of the clinical development of PS433540 is to combine the potentially synergistic action of
“angiotensin receptor blockade” with
“endothelin receptor antagonism” for the clinical use in HTN and Diabetic Nephropathy.
Stage I HTN: SBP equal/greater than 140 to equal/less than 159 / DBP equal/greater than 90 to equal/less than 99
Stage II HTN: SBP equal/greater than 160 / DBP equal/greater than 100
Angiotensin II (AII) and
endothelin 1 (ET1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including hypertension, diabetic nephropathy and heart failure. Currently,
angiotensin receptor blockers (ARBs), which block the activity of AII, are widely used as a treatment for hypertension, diabetic nephropathy and heart failure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of
ET receptor antagonists (ERAs) in blocking ET1 (Endothelin) activity (AKA:
ERBs for Endothelin Receptor Blockers).
It is also known that AII and ET1 work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of AII at its receptor, but also limit the production of ET1. Similarly, ERAs block ET1 activity and inhibit the production of AII. Consequently, simultaneously blocking AII and ET1 activities may offer better efficacy than blocking either substance alone.
In well-validated rat models of human hypertension, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the co-administration of an ERA has been reported by a third party (other than Pharmacopeia) in Phase 2 clinical development.
Pharmacopeia's lead internal development candidate (PS433540), which was licensed from Bristol-Myers Squibb, appears to block the activity of both AII and ET1 at the AT1 and ETA receptors, respectively. It is the first and only example of a single compound with dual-acting angiotensin and endothelin receptor antagonist (DARA) activity in development. Pharmacopeia views PS433540 as a first-in-class product candidate, which may represent a significant advancement in the treatment of cardiovascular disease. A number of preclinical studies using PS433540 have resulted in positive outcomes in multiple disease models and a positive preclinical pharmacokinetic and safety profile.
The company has announced positive results from multiple Phase 1 clinical studies for PS433540. Results from a single ascending dose study indicated that the compound was well tolerated at all six doses administered ranging from 20 mg to 1,000 mg and that the compound has a half-life that is consistent with once daily administration. In the multiple ascending dose study, five dose levels from 50 mg to 1,000 mg have not produced safety or tolerability issues. In an AII challenge study, PS433540 demonstrated its ability to block the increase in blood pressure induced by administration of angiotensin II (AII) to healthy volunteers. Numerous similar studies with other agents that block the renin-angiotensin system support that the result is a strong indication that PS433540 can be expected to lower blood pressure in hypertensive patients.
Pharmacopeia Inc. (Princeton, NJ) started a Phase IIb trial of PS433540, a dual-acting angiotensin and endothelin receptor antagonist, in patients with stage I and stage II hypertension. The randomized, double-blind, placebo- and active-controlled study is enrolling about 375 subjects, who receive 200, 400 or 800 mg PS433540, 300 mg of the angiotensin II receptor blocker irbesartan or placebo once a day for 12 weeks. Investigators will evaluate change from baseline in mean seated systolic blood pressure and other blood pressure measures. Results from a Phase IIa study of PS433540 in patients with stage I and stage II hypertension are expected in the second quarter of this year. The compound works by selectively blocking the action of two potent vasoconstrictor and mitogenic agents, angiotensin II and endothelin A, at their respective receptors. In Phase I trials, it was well tolerated at single doses ranging from 20 to 1,000 mg and at multiple daily doses of up to 500 mg. It is also a potential treatment for diabetic nephropathy.
30 January 2008
VERSION: 1 2 3 4 5 6 7 8 9
DARA: Dual Acting Receptor Antagonist ARB + ERB
Questions
- Indemnification: The sponsor likes to be held harmless for acts of negligence that the PI commits that are solely the error of the treating physician. For example, if a PI treats a subject's UTI during a study and the patient suffers an injury from this, it is squarely the PI’s fault and it would not be proper for the sponsor to sustain an injury by being held liable for it. However, we are aware of a BP study where the PI followed the protocol and had the subject wash off their BP medication and suffer a stroke from the lack of the proper BP treatment. The sponsor forced the PI to use his medical malpractice insurance to satisfy the claim for medical malpractice. Clearly, this was an injustice as the PI was following the protocol precisely and even though it is unusual for a stroke to occur during wash out, it certainly does not immunize the subject from having a stroke. When a stroke occurs during wash out it is important that the sponsor take responsibility for the liability. This should be true of any injury ex officio of changing a subject’s treatment while following the protocol. If this drug causes respiratory depression, are you going to be fully liable?
- Study Fully Populated Causing Premature Early Termination: As sites advertise for patients to become research volunteers, the people that are good enough to step forward to join, wash off of their existing treatment, come to our site and devote a significant amount of their time with blood draws, signing paperwork and allowing the experimental protocol to progress, should be guaranteed that the sponsor will not prematurely shut down the study because they have obtained the needed number of subjects. That is, it should be the sponsor’s responsibility to do the number crunching early enough not to allow subjects to sign consent and undergo early termination just because the study is now considered full enough. This is not ethical or in the patients best interest. All subjects who sign consent must be allowed to continue thru the protocol if they are continuing to fulfill criteria regardless of how many subjects are in the trial.
- Reimbursement for Screen Failures: Sites are taking finincial risk in the name of enrolling only those subjects who will successfully complete the trial. Sponsors need to recognize that this significantly slows enrollment. When we see a subject who may qualify but then again may not, we would be hesitant to enroll in that study. Since the exclusivity clock starts clicking as soon as the drug is patented it is imperative that the studies are done as quickly as possible. Sites that are rewarded for each piece of work they legitimately perform will have to enroll better. Sites with too high screen failure rates can be turned off to ensure the proper motivation to enroll high quality subjects is present.
- Sponsor Early Term Study: Should the Sponsor ET the study after the site has put a significant amount of work into preparing for it, what finincial arrangements are being thought of to compensate the site? After all, we found the trial, reviewed the IB, isolated potentially eligible subjects and advertised. The rest of the study is the relatively easy part. This goes along with start-up cost reimbursement. There should be a fee paid to the sites for start-up costs to help defray this potentiality. Paying more per subject to compensate for start-up costs leaves the site liable for the costs related to the sponsor unilaterally stopping the trial.
- Initial Fasting Labs and Informed Consent: Many trials have “visit one” with fasting labs and signing informed consent on the same day. This is less desirable than having a visit one where the subject presents non-fasting for the purpose of signing the informed consent form and having the study discussed with them. The potential problem is with a diabetic. If a diabetic patient answers an ad and presents fasting for visit one, a research related procedure was done prior to signing the ICF (Informed Consent Form). They could get a low sugar reaction while driving to the site and suffer an MVA. They may also feel pressured to sign the ICF quickly as they know when the do so they will finally get something to eat. This can be most safely avoided by allowing subjects to sign the ICF on a pre-visit one or by writing protocols that don't have fasting labs as a visit one procedure. Although I understand V1 labs are non-fasting for this trial.
- Recruitment: Too often recruitment is an oversight thought to be the sites problem dealt with at a time other than the beginning of the trial. It becomes the sponsor’s problem after many sites under enroll. Wise sponsors address recruitment up front at the investigator’s meeting and include recruitment agencies. One budget neutral solution is for the sponsor to push to make available an IRB approved ad for those using the central IRB at the very beginning of the trial. In addition use of centralized recruitment agencies like Pi and Acurian can very useful and cost effective. All our databases could be larger. A small minority of people step forward to become research subject volunteers. Planning for recruitment issues at the beginning is much better than catch up at the end.
Impediments to Enrollment
- The one month wash out phase does scare some subjects away & out of the study. When they see their BP up, it frightens them. We of course reassure them but this is an impediment.
- V4 being a four hour visit is an impediment to enrollment. Perhaps an ABPM could obviate the need for this.