Clinical Trials

STOP-ALF

ALFSG-OCR-002: A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (ornithine phenylacetate) in the Treatment of Patients with Acute Liver Failure/Severe Acute Liver Injury (STOP-ALF).

This is a Phase 2a, multi-center, open-label study, conducted in two cohorts of patients diagnosed with acute liver failure/severe acute liver injury (ALF/ALI) who meet inclusion/exclusion criteria. Cohort 1 is defined as patients with ALF/ALI with minimal renal dysfunction at the time of enrollment (defined as a serum creatinine ≤1.5 mg/dL and mean arterial pressure of >65 mm Hg). Cohort 2 is defined as patients with ALF/ALI with compromised renal function (defined as a serum creatinine >1.5 mg/dL and <10 mg/dL with mean arterial pressure of >65 mm Hg after correction of hypovolemia).

Informed consent will be obtained from the patient and/or patient’s legally authorized representative (LAR) or family member as defined in 21CFR50.3(m). All patients will receive medical care for acute liver failure/severe acute liver injury according to the institution’s standards of care. Standard of care may include, but is not limited to, administration of N-acetylcysteine and consideration for orthotopic liver transplantation.

Up to 24 evaluable patients are to be enrolled. An evaluable patient is one who has received an infusion of OCR-002 for at least 72 hours. Dosing with OCR-002 may be initiated immediately after obtaining signed informed consent; or, up to 32 h after obtaining consent should the time be necessary to complete any pre-study drug initiation requirements and/or to provide a time frame for study drug administration.

Baseline is immediately prior to the start of the initial infusion. At Treatment Day 1 - Time “0” (T0) and after baseline measurements, each patient will receive an initial infusion rate of OCR-002. Dose will be escalated to a maximum dose of 10g/24h infusion as indicated herein. Titration of dose will depend on evidence of safety and tolerability (refer to Treatment section below).

Patients may have an IV catheter inserted as a safer and easier method for obtaining repeated blood sampling and a separate IV for the infusion. Blood samples for measurement of plasma ornithine, phenylacetate and PAGN concentrations will be collected at multiple time-points during the infusion period, at the completion of the iast infusion and up to 24 hours following the completion of the last infusion. Urine will be collected at specific intervals to determine the amount of PAGN excreted.

Patients will be assessed for safety and tolerability of OCR-002 as well as pharmacokinetic and pharmacodynamic variables during the infusion period, at the completion of the last infusion and 24 hours following the completion of the last infusion. Data on clinical outcomes will also be collected during the study period.

Safety data will be reviewed by a Safety Review Committee (SRC) operating under an approved charter and made up of three ALFSG clinicians who are independent of the participating clinical sites and a clinical pharmacologist with experience in PK and clinical trials. Throughout the trial, the SRC will review all safety data at regular intervals, and the FDA will receive annual IND reports.

Supportive Care

Inotropic support will be used to maintain mean arterial pressure above 65 mm Hg in patients who become hypotensive after enrollment. Dialysis or continuous veno-venous hemofiltration (CVVH), endotracheal intubation and mechanical ventilation will be considered as indicated. Cerebral edema will be managed post-enrollment with mannitol or hypertonic saline per local institutional practices. Antibiotic therapy may be initiated and modified as required. In patients who have intracranial pressure (ICP) monitors placed, ICP, cerebral perfusion pressure and mean arterial pressure will be recorded continuously and reported hourly.

OCR-002 (ornithine phenylacetate) will be supplied to the Investigator by Ocera Therapeutics, Inc., Durham, NC.

Introduction and Background

Acute liver failure (ALF) is a rare disorder affecting an estimated 2000 patients annually in the United States (US). Hepatotoxicity related to the use of acetaminophen is the most common etiology of ALF in the US (1).

Acute liver failure is the result of massive damage to previously normal liver parenchyma with resultant loss of liver function. As the hepatocyte function is lost, the liver loses its ability to synthesize proteins and extract circulating toxins. The two cardinal signs of ALF, coagulopathy and encephalopathy, represent the loss of the ability to synthesize clotting factors and to remove ammonia, respectively.

Acute liver failure often affects young people and carries a very high mortality. Only 45% of patients with ALF will spontaneously recover. Of the remaining 55%, 30% will die and 25% will undergo an emergency liver transplantation. Emergency liver transplantation in this setting has a 90% 1-month survival rate and a 70% 1-year survival rate. Mortality in ALF can be due to a variety of factors, including sepsis and multi-organ system failure, but cerebral edema due to increased ammonia resulting in intracranial hypertension and brainstem herniation is one of the most common causes of death, accounting for 30% of the mortality in this population (2).

There is strong experimental and clinical rationale for the use of ammonia-lowering therapies in ALF. Ammonia is normally produced in the gut and transformed by the liver into urea. As the liver fails, ammonia increases in the systemic circulation and enters into the brain. The result of a rapid rise in ammonia in the cerebral circulation is hepatic encephalopathy (HE), a reversible neuropsychiatric condition that ranges in severity from mild impairment in attention, to delirium, coma and death. A particular concern regarding HE in ALF is that ammonia level increases tend to be very rapid. This rapid rise in ammonia does not provide sufficient time for brain cells to compensate, with the end result being astrocyte swelling with increased intracranial pressure (ICP) and ultimately, death due to brain herniation. An arterial ammonia level above 150 μM has been shown to correlate with a poor prognosis, and is almost universally indicative of increased intracranial pressure (3).

Cerebral edema in patients with ALF results from overloading brain astrocytes with ammonia. Astrocytes utilize the same mechanism as skeletal muscle to detoxify ammonia (i.e., amidation of glutamate to glutamine via glutamine synthetase). The resulting accumulation of brain glutamine results in impaired astrocyte osmoregulation, astrocyte swelling and cerebral edema (4-6). Astrocytes contain counter-regulatory mechanisms to offset increased intracellular osmotic pressure, but compensate too slowly in the acute situation.

Cortical astrocyte swelling is the most common neuropathological observation in post-mortem brains of ALF patients. Cerebral edema is found in up to 80% of patients who die of ALF and is nearly universal among patients with coma (7).There are clear associations between arterial ammonia levels, uncal herniation, and death in patients with ALF (3,8). There is also clear evidence of these associations in animal models of ALF(9-12).

OCR-002 (L-ornithine·phenylacetate) is an ammonia detoxification agent that works by eliminating ammonia in the circulation, with the expectation that it will result in a more rapid reduction than current therapies, and a lower incidence of cerebral edema.

3.2 Physical, Chemical, and Biological Characteristics of OCR-002

Background information on OCR-002 is summarized below. More detailed information is provided in the Investigator’s Brochure.

3.2.1 Chemistry

OCR-002 is an ammonia detoxification agent and has the chemical name L-ornithine·phenylacetate (L-ornithine·benzeneacetate salt (1:1), CAS-RN 952154-79-9). The molecular formula is C8H7O2·C5H13N2O2and OCR-002 has a molecular weight of 268.31 g/mole.

OCR-002 drug substance is a new chemical entity and exists as a single crystalline molecular structure as an ornithine salt ofphenylacetate as shown below:

Figure 1: L-ornithine·phenylacetate

Summary of Nonclinical Safety Data

The nonclinical safety of OCR-002 was evaluated in a comprehensive program of in vitro and in vivo studies which included evaluation of the potential undesirable pharmacodynamic effects of OCR-002 on physiological functions in relation to exposure in the therapeutic range and above (safety pharmacology core battery), evaluation of the mutagenic and clastogenic potentials of OCR-002 (in vitro test battery for genotoxicity), and evaluation of the short- and longer-term functional and morphologic effects associated with OCR-002 exposure in whole animal models (mammalian toxicology program). The results of the OCR-002 toxicology program indicate a low potential for systemic toxicity in humans. Please refer to the OCR-002 Investigator’s Brochure for a detailed discussion.

Further evidence of safety is provided by over 20 years of clinical experience with Ammonul® (sodium phenylacetate and sodium benzoate) Injection 10%/10% and Hepa-Merz™ (L- ornithine L-aspartate). The safety profiles of these entities are discussed in the Investigator’s Brochure.

Rationale for the Study

There is no established medical therapy for ALF (13). Investigational agents such as charcoal hemoperfusion and administration of prostaglandin E1, which showed early promise, have not been shown to be superior to standard of care when analyzed in randomized controlled studies (14-17). Plasmapheresis and hepatectomy have been suggested as possible “bridges” to liver transplantation but a prospective trial of the former has been presented in abstract form only. Hypothermia has been investigated in a total of only 38 patients with ALF, all from Jalan, et al (18), and may be an effective bridge to liver transplantation (19). However, therapeutic hypothermia has considerable potential adverse effects and has never been shown to increase spontaneous (non-transplant) survival. External bio-artificial livers such as the MARS device have been employed, but use of these devices remains experimental, and the preliminary results have been generally disappointing (20).

Treatment strategies focusing on the specific underlying conditions are, for the most part, of little or no use once ALF has occurred. Corticosteroids for fulminant autoimmune hepatitis, chelation therapy for fulminant Wilson’s disease, and anti-viral therapies for fulminant hepatitis B have never been shown to be of benefit in the setting of ALF, and supportive care and liver transplantation are the only treatment strategies that can be used in these patients (21-23).

One notable exception to this is the use of N-acetylcysteine (NAC) for ALF due to acetaminophen overdose. NAC, a glutathione donor, is the antidote for acute acetaminophen toxicity, and it has been shown to improve outcome in these patients. Importantly, it is most effective if administered within 8-24 hours of the overdose (24), which significantly limits its therapeutic impact. It is mainly of benefit in patients who take an intentional overdose and then present rapidly for medical care. Cases of accidental overdoses often present for medical attention after the effective window for NAC has closed. Similarly, patients taking an intentional overdose who do not seek care often present too late for NAC to be of maximum benefit (25). Recently, a controlled blinded study of NAC has shown evidence that it benefits non-acetaminophen-related ALF if given during early stages of encephalopathy (26).

Thus, for the vast majority of patients with ALF, liver transplantation is the only recognized treatment option. However, some patients cannot be transplanted due to the severity of their disease or a concomitant medical condition, and even patients who are listed may die waiting for a suitable organ to come available. Transplantation is far from an ideal treatment, as short-term survival for patients with ALF is lower than for cirrhosis, with a 90% 1-month survival and 70% one-year survival (27, 28). Transplantation also commits the patient to a lifetime of immune-compromising and toxic anti-rejection medications. Additionally, some neurocognitive sequelae of increased intracranial pressure persist after liver transplantation for ALF.

In summary, therapeutic options in ALF are limited other than supportive care and liver transplantation. NAC is appropriate for early presentations of acetaminophen overdose and possibly is of value in other forms of ALF. Management of fluid status, airway protection and infection control are important, and, for cerebral edema, mannitol or hypertonic saline are used to osmotically draw water from astrocytes, but are temporizing measures (28). Usually, patients with intracranial hypertension who initially respond to mannitol or hypertonic saline die of cerebral herniation if not transplanted in short order.

The above observations provide a strong rationale for using ammonia-lowering therapy in patients with ALF. Lactulose is widely used for this purpose in patients with cirrhosis, but has not been studied systematically in patients with ALF, and may obscure the surgical field at the time of liver transplantation due to gaseous distention of the bowel (28). Poorly absorbable antibiotics such as neomycin or rifaximin have also not been studied, and the former carries considerable risk of nephrotoxicity. A recent randomized, controlled study of L-ornithine L- aspartate (LOLA), a putative ammonia-lowering agent, found no improvement in blood ammonia concentrations or survival in patients with ALF (29). However, the rationale underlying the use of this agent may be flawed, since the compound provides a substrate (ornithine) for the production of glutamate and theoretically may lower ammonia by production of glutamine, but does not provide a route of glutamine elimination from the body. Thus, glutamine persists in the circulation in patients receiving LOLA, and subsequently may be de-amidated back to ammonia and glutamate by gut glutaminases (30).

OCR-002 (ornithine·phenylacetate; OPA) is an ammonia detoxification agent with a better rationale for use in patients with hyperammonemia than LOLA. In contrast to LOLA, OPA not only provides a substrate for the synthesis of glutamate and thus glutamine, but also a route of elimination of glutamine in the urine as phenylacetylglutamine (PAGN) (14). The synergistic effects of L-ornithine and phenylacetate have been documented in validated pharmacology models of liver failure, the devascularized ALF pig and the bile duct ligated cirrhotic rat. In these animal models, reduction of the central target of OPA, ammonia, correlated with improvement in intracranial pressure and frontal brain water, which are associated with HE, as well as morbidity and mortality in humans with ALF. The mechanism supporting elimination of glutamine via PAGN in urine has been confirmed in both models and supports the utility of the combination therapy for removal of waste nitrogen (ammonia) from the body. Another important feature of OPA pertains to the ability of PAGN to be dialyzed, a critical observation as many patients with ALF develop acute renal failure requiring renal replacement therapy.

Patients with acetaminophen toxicity leading to acute liver injury or liver failure are optimal patients for the planned clinical study for several reasons. First, their liver injury is severe and occurs very rapidly over a prescribed time course, considered hyperacute (< 7 days) in duration. Second, acetaminophen patients comprise a large, relatively homogeneous patient group, are typically young and otherwise healthy. Third and most importantly, they are at the highest risk for elevated ammonia levels and cerebral edema because of their young age and the rapidity of their liver failure. Renal failure can also be observed in this setting, presumed due to a direct effect of the drug on the renal tubular cells, and contributes to hyperammonemia and the risk of cerebral edema. Although the overall recovery rate is quite high after acetaminophen overdose despite the severity of the liver injury, many patients cannot be listed for transplantation because of the psychosocial issues which contributed to the overdose.

In the current protocol, all patients will have been treated with NAC as standard-of-care for acetaminophen toxicity. There are no anticipated interactions between NAC and OCR-002 based on the pharmacology of each compound. All patients who are enrolled will have received appropriate management for acetaminophen toxicity, including N-acetylcysteine either oral or intravenous, prior to study enrollment. In some instances, this will be continued during, or may overlap with, the study period.

This Phase 2a clinical study is designed to provide data on OCR-002 in patients with ALF/ALI in regard to:

(a) safety and tolerability;

(b) metabolism of the compound to glutamine and phenylacetylglutamine;

(c) its effect on circulating ammonia levels and neurological function in patients with and without impaired renal function after continuous infusion at different infusion rates.

It is anticipated that this early safety and tolerability study, with appropriate PK/PD data, will lead to a development program for the use of OCR-002 in the treatment of hyperammonemia either due to ALF or even more generally, for ACLD.

References

1. Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28:142-152.

2. Roberts MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L. Survival after liver transplantation in the United States: a disease-specific analysis of the UNOS database. Liver Transpl 2004;10:886-897.

3. Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol 2009;6:542-553.

4. Blei AT. Pathogenesis of brain edema in fulminant hepatic failure. Prog Liver Dis 1995;13:311-330.

5. Jalan R. Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochem Int 2005;47:78-83.

6. Larsen FS, Wendon J. Prevention and management of brain edema in patients with acute liver failure. Liver Transpl 2008 Oct;14 Suppl 2:S90-S96.

7. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999;29:648-653.

8. Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999;31:771-776.

9. Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 2006;55:98-104.

10. Traber PG, Dal Canto M, Ganger DR, Blei AT. Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier. Hepatology 1987;7:1272-1277.

11. Cordoba J, Gottstein J, Blei AT. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology 1996;24:919-923.

12. Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L- aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 1999;30:636-640.

13. Rose C, Michalak A, Pannunzio M, Chatauret N, Rambaldi A, Butterworth RF. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology 2000;31:872-877.

14. Jalan R, Wright G, Davies NA, Hodges SJ. L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 2007;69:1064-1069.

15. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179-1197.

16. Sterling RK, Luketic VA, Sanyal AJ, Shiffman ML. Treatment of fulminant hepatic failure with intravenous prostaglandin E1. Liver Transpl Surg 1998;4:424-431.

17. O'Grady JG, Gimson AE, O'Brien CJ, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988;94:1186-1192.

18. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology 2004;127:1338-1346.

19. Stravitz RT, Larsen F. Therapeutic hypothermia for acute liver failure. Crit Care Med 2009: 37(7 Suppl):S258-6.

20. McKenzie TJ, Lillegard JB, Nyberg SL. Artificial and bioartificial liver support. Semin Liver Dis 2008;28:210-217.

21. Randomised trial of steroid therapy in acute liver failure. Report from the European Association for the Study of the Liver (EASL). Gut 1979;20:620-623.

22. Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007;45:97-101.

23. Ichai P, Duclos-Vallee JC, Guettier C, Hamida SB, Antonini T, Delvart V, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007;13:996-1003.

24. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen- induced hepatotoxicity (1987-1993). Gastroenterology 1995;109:1907-1916.

25. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364-1372.

26. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non- acetaminophen acute liver failure. Gastroenterology 2009;137:856-64, 864.

27. Liou IW, Larson AM. Role of liver transplantation in acute liver failure. Semin Liver Dis 2008;28:201-209.

28. Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007;35:2498-2508.

29. Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L- aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009;136:2159-2168.

30. Jalan R, Lee WM. Treatment of hyperammonemia in liver failure: a tale of two enzymes. Gastroenterology 2009;136:2048-2051.