Kevin Grimes

Protein kinase C, an elusive therapeutic target?

Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications — including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder — were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

Background— KAI-9803, a &dgr;-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Methods and Results— Direct Inhibition of &dgr;-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a “first-in-human,” dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in 99mtechnetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3. Conclusions— KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.

Myocardial salvage in acute myocardial infarction - Challenges in clinical translation

In 2001, the Mochly-Rosen laboratory published the first evidence that inhibition of delta protein kinase C (δPKC) at the onset of reperfusion reduced tissue injury in preclinical models of acute myocardial infarction (AMI). In various models of cardiac ischemia and reperfusion (I/R)including cultured neonatal cardiac myocytes [1], ex vivo whole rat heart [2], and in vivo porcine heart [3], we demonstrated that delivering a rationally designed peptide allosteric inhibitor of δPKC (δV1-1) at reperfusion reduced infarct size by about 70% [3]. δV1-1 treatment reduced necrosis and apoptosis, accelerated ATP regeneration, preserved mitochondrial structure, and preserved organization of contractile elements [3–6]. We also found that treatment with δV1-1 protected the vascular endothelium, leading to improved microvasculature flow and rapid recovery of coronary flow reserve [5]. All the benefits of δV1-1 treatment delivered at ~500 ng/kg at reperfusion were sustained through 12 days after treatment, including a ~70% smaller infarct size than control, normal ejection fraction, and normal coronary flow reserve [5]. Finally, independent studies that contributed to the characterization of δPKC in reperfusion injury in the heart were carried out in the laboratories of Drs. Gerald Dorn and Roberto Bolli [1], and Elizabeth Murphy [5], and were also corroborated independently using other systems, e.g. when using human atrial trabeculae strips in a transient ischemia model[7]. This preclinical evidence together with δV1-1’s excellent safety profile led KAI pharmaceuticals to test whether similar benefits could be achieved in AMI patients. The DELTA MI trial was a first-in-human, double-blinded, placebo controlled phase 1/2a trial to assess the safety of intracoronary δV1-1 (KAI-9803) in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). (For patient characteristics and detailed trial design, see ref [8].) Drug administration was based on the porcine STEMI model, in which the peptide was delivered through the lumen of a balloon catheter to the area down-stream of the occlusion, just prior to balloon deflation. Based on discussions with the FDA and bridging animal studies, a second dose was given through the guide catheter after balloon deflation, to allow drug delivery to myocardium supplied by arterial side branches that might have been blocked by the inflated balloon. The trial included five arms: a concurrent placebo arm of 51 patients and 4 drug-treated arms of 0.05, 0.5, 1.25, and 5 mg, with 25–26 patients each. The lowest dose was calculated to be efficacious based on the porcine model. DELTA MI demonstrated that δV1-1 was safe at all dose levels tested. Although the trial was not designed to achieve statistical significance, a trend towards benefit was seen in biomarkers that correlate with AMI clinical outcomes when the combined treatment groups were compared to placebo. These biomarkers included resolution of ST segment elevation, as measured by ST segment area under the curve (AUC), and infarct size, as measured by creatine kinase AUC (Figure 1; summarized from data in [8]). Late ischemic events (as measured by ST segment re-elevation in the 24 hrs after treatment) also declined by 63% (unpublished data). Figure 1 DELTA MI Biomarker Results These encouraging data on the safety and potential efficacy of δPKC inhibition led to a phase 2b trial testing intravenous δV1-1 in STEMI patients undergoing primary angioplasty (sponsored by KAI Pharmaceuticals with Bristol-Myers Squibb). The rationale for switching from intracoronary to intravenous administration was three-fold: 1) to allow earlier and more timely drug delivery to the increasing percentage of patients (up to 40%) who were achieving partial reperfusion prior to PCI as evidenced by TIMI 2/3 flow on initial angiography; 2) given δV1-1’s exceptionally short serum half-life (<2 minutes), continuous intravenous infusion allowed longer exposure of ischemic myocardium to the drug with the potential to increase efficacy, and 3) ease of use for the treating cardiologists. The trial sponsors had performed further preclinical [9]and human phase 1 studies to predict efficacious dose range and duration of therapy, establish safety, and characterize pharmacokinetics of intravenous infusion of δV1-1. The PROTECTION AMI trial enrolled 908 patients across four groups (~227 patients/group). Subjects received a 2.5 hour infusion of placebo or one of three doses (125, 375 or 1125 mg)of δV1-1 (called delcasertib in the trial). Preliminary results of PROTECTION AMI were presented at the American College of Cardiology meeting in March, 2011. The data showed that the inhibitor was safe at all doses tested, but failed to show a statistically significant benefit in the primary endpoint of CK-MB area under the curve with δV1-1 administration. Subgroup analysis revealed a trend towards reduced infarct size (~14%) in the two highest doses in patients with anterior MI and TIMI 0/1 flow on initial angiography, which represented 60–65% of the patients in each treatment arm [10]. Although the full analysis of PROTECTION MI has yet to be completed and published, several issues may inform the design of future myocardial salvage studies.

Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries

With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need.

Human Chitotriosidase Does Not Catabolize Hyaluronan

Humans express an enzyme that degrades chitin, called chitotriosidase, despite the fact that we do not produce chitin. One possible explanation for this is that chitinase also degrades hyaluronan, a polysaccharide that is abundant in human tissues and shares structural attributes in common with chitinase. The objective of this study was to determine whether human chitotriosidase is capable of hydrolyzing hyaluronan. Hyaluronan of various sizes under a range of pH conditions displayed no degradation when incubated with various chitinases over a period of 5 days, while commercial hyaluronidase readily digested the hyaluronan. Under the same conditions, recombinant chitinase but not our negative control chitinase, was able to digest chitosan. We conclude that human chitinase does not digest hyaluronan. Because chitin is a prominent component of certain fungi and insects, it seems likely that human chitinase evolved for roles in host defense rather than serving to catabolize the endogenous polymer hyaluronan.

Identificación, diagnóstico y tratamiento de la hiperhidrosis primaria localizada *

Resumen La hiperhidrosis primaria localizada es una enfermedad que se caracteriza por una sudoracion (transpiracion) excesiva, bilateral y relativamente simetrica, que aparece en axilas, palmas de las manos, plantas de los pies y region craneofacial. Este trastorno puede acarrear problemas laborales, psicologicos y fisicos, asi como, eventualmente, constituir un estigma social.