Physicians' Financial News

Onyx Flourishing on Strength of Single Agent With Multiple Applications

Physician’s Financial News

In each issue, focuses on a news-making and/or notable company in the oncology biotechnology sector. Typically, the featured concern will boast a sizable portfolio of oncology products and product candidates, including numerous FDA-approved agents on the market and an additional complement of compounds in the development pipeline. Next month’s issue, for example, will spotlight Abbott Laboratories, a company so huge that its U.S. and world-wide pharmaceutical business comprises only one of several stand-alone divisions, each of which offers more products and is larger in size than most whole companies.

This month’s featured company, Emeryville, California—based Onyx Pharmaceuticals, Inc., however, has taken a different strategic approach toward competing in the sector. Although the Onyx research and development (R&D) department is continually pursuing new therapies—in fact, a novel experimental drug, discovered and developed inhouse, has just entered early- stage clinical trials (more on this agent to follow)—the company has recognized that its lead product, Nexavar (sorafenib), is a multifaceted therapy with a number of potential applications in a wide-ranging variety of cancers. Therefore, the bulk of Onyx’s R&D efforts center upon expanding Nexavar’s potential to the fullest and most complete extent possible.

This month’s feature, then, in addition to fulfilling its regular function as corporate profile, also serves as a sort of experimental industry case study on alternative, unorthodox market strategy. How does the performance of a company (i.e., in terms of financials, industry position, future prospects, etc.) that chooses a narrow, targeted R&D focus designed to fully reap the benefits of one particularly fertile agent compare with competitors who have adopted more traditional approaches? The answer, insofar as it can be determined in the sections that follow (pipeline prospects, financial performance, sales, etc.) is: surprisingly well.

Products and Pipeline

The purpose of Onyx Pharmaceuticals, founded in 1992, according to a statement published on its website, is to engage in the discovery, development, distribution, and marketing of “innovative small molecule cancer treatments based on a molecular understanding of cancer.”

Onyx’s lead product is Nexavar, an agent that is being developed and marketed in collaboration with Bayer HealthCare Pharmaceuticals. The orally delivered (tablet formulation) multiplekinase inhibitor targets proteins involved in both tumor cell proliferation and angiogenesis. In preclinical studies, Nexavar has been shown to inhibit the enzyme RAF kinase, which is a critical component of the RAS pathway—an important cascade of chemical signals that controls cell division. Abnormal activation of the RAS pathway is believed to play an integral role in the genesis of many cancers. Additionally, Nexavar inhibits VEGFR-2 and PDGFR-ß, key receptors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which play important roles in angiogenesis. Nexavar also inhibits other tyrosine kinases such as c-KIT and FLT-3.

To date, Nexavar is approved in more than 60 countries (including the European Union) for the treatment of patients with advanced kidney cancer. The drug has been an FDA-sanctioned kidney cancer therapy since December 2005. Nexavar's approval in the United Stated followed a report at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO), demonstrating that Nexavar was generally well tolerated and significantly delayed disease progression in an ongoing phase III clinical trial in patients with advanced kidney cancer. As assessed by independent radiologic review, progression-free survival (PFS) was doubled to a median value of 24 weeks (167 days) in patients receiving Nexavar, compared with 12 weeks (84 days) for patients receiving placebo.

More recently (in November of last year), Nexavar gained a second indication to treat liver cancer in the United States and (shortly thereafter,) the E.U. The approvals were based on positive data from the international, phase III, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, which demonstrated that Nexavar extended overall survival in patients with hepatocellular cancer (HCC), or primary liver cancer, versus those taking placebo by 44%. Presented at the ASCO annual meeting, Chicago, in June 2007, these data showed that median overall survival for Nexavar-treated patients was 10.7 months, compared with 7.9 months in those taking placebo.

According to an Onyx spokesperson, the oral anticancer drug is the first approved systemic therapy for liver cancer and the only one on the market that has been shown to significantly improve overall survival in patients with the disease. In comments made shortly after the liver indication was obtained, Hollings C. Renton, outgoing chairman, president and chief executive officer, Onyx Pharmaceuticals, Inc. (Mr. Renton is set to retire as of April 2008. N. Anthony Coles, MD, is his replacement.), stated, “Liver cancer is one of the cancers in which the number of related deaths continues to increase. This second approval for Nexavar demonstrates our commitment to expediting the clinical development of this innovative therapy to treat today's unmet needs in cancer."

As part of a broad development program, Nexavar is also currently being evaluated in randomized trials in non—small cell lung cancer, breast cancer, melanoma, and many other tumor types. Onyx also has a second product in clinical testing, a small molecule cell cycle inhibitor that resulted from a collaboration with Warner Lambert, a Pfizer subsidiary.

Although Onyx’s development pipeline may not be as deep as those of its competitors (in terms of number of current agents segmented into trial phases, working their way toward market), it is extremely wide ( as far as the number of potential new and expanded indications that are being evaluated).

Currently, there are 17 separate ongoing clinical trials (in all phases) assessing the efficacy and safety of the company’s major product, Nexavar, both as monotherapy and as a component of various novel combinations and formulations, in a diverse array of new and expanded indications for multiple types of treatment scenarios, disease stages, degrees of severity, and malignancies, including liver cancer (two trials), kidney cancer (four trials), non—small cell lung cancer (four trials), melanoma (two trials), and breast cancer (five trials).

In addition, the company is nearing the end of phase I testing and preparing to transition into phase II analysis of PD 332991, a cell cycle kinase inhibitor (also known as a cyclin-dependent kinase inhibitor), developed in conjunction with Warner-Lambert Company, that is being looked at in a variety of solid tumor cancers.

Company Financials

In a recent conference call with investors, Onyx disclosed financial results. Seen through the prism of no-nonsense, bottom-line metrics such as annual earnings, Onyx’s almost willfully contrarian lack of product diversification begins to look downright visionary. Despite (or, perhaps, because of) the company’s single-product emphasis, Onyx was able to outperform and outgrow a significant proportion of its competitors, most notably in the categories of net sales and net sales growth. Although the company, like many of its oncology biotechnology counterparts, sustained an overall loss in 2007, it made a great deal of year-over-year progress toward closing its profitability gap.

Nexavar net sales were $124.9 million for the quarter ended December 31, 2007, which represents a 96% increase over the $64 million reported in the same period in 2006 and a 19% increase over the $105 million reported in the quarter ended September 30, 2007. For 2007 as a whole, Nexavar net sales were $372 million, a 125% increase over the $165 million reported in 2006.

“We are pleased with Nexavar’s continued commercial growth, generating worldwide net sales of $125 million for the fourth quarter and $372 million for 2007. The approvals of Nexavar in liver cancer and advanced kidney cancer reinforce our commitment to invest in Nexavar, both commercially and clinically, to maximize the full value of this proven anticancer agent,” said Mr. Renton.

In the fourth quarter of 2007, Onyx recorded R & D expenses of $5.5 million, a decrease of $1.3 million compared with the fourth quarter of 2006. Fourth quarter 2007 selling, general, and administrative expenses were $16 million, an increase of $3.3 million as compared with the fourth quarter of 2006. The increase in selling, general and administrative expenses was primarily attributed to a planned increase in the commercial and administrative personnel to support Nexavar.

A net loss of $0.21 per share was reported for the fourth quarter of 2007, compared with a net loss of $0.47 per share, during the same period in the prior year. For the twelve months ended December 31, 2007, Onyx recorded a net loss of $0.67 per share, compared with a net loss of $2.20 per share, for the same period in 2006.

Despite Onyx’s steady rate of growth and the company’s inroads toward profitability, the equity has seen its fair share of volatility over the past 12 months. Through March and April, the volatile stock stabilized and even recovered somewhat. The stock, which has been showing signs that it is likely to rally further, in a weak but sustained manner, has been steadily but slightly trending upwards through the month of April 2008 (increasing from less than $30 per share at the beginning of the month, to the point where, at midmonth, it had been flirting with a valuation of $35 per share).

Onyx Oncology Pipeline

Drug

Cancer Type

Phase I

Nexavar (sorafenib)/

carboplatin/Alimta

First-line non-smallcell lung cancer

PD 332991

Various types of cancer

Phase II

Nexavar (sorafenib)/

doxorubicin

First-line liver cancer

Nexavar (sorafenib)

Kidney cancer (dose escalation)

Nexavar (sorafenib)/

various combinations

Kidney cancer

Nexavar (sorafenib)/

Alimta

Second-line non-small cell lung cancer

Nexavar (sorafenib)

Second and third-line non- small cell lung cancer

Nexavar (sorafenib)/

temozolomide

Melanoma (multiple lines)

Nexavar (sorafenib)/

paclitaxel

First-line breast cancer

Nexavar (sorafenib)/

capecitabine

First and second-line breast

cancer

Nexavar (sorafenib)/

gemcitabine

First and second-line breast

cancer

Nexavar (sorafenib)/

docetaxel and/ or

letrozole

First-line breast cancer

Nexavar (sorafenib)/

aromatase inhibitors

First and second-line breast

cancer

Phase III

Nexavar (sorafenib)

Liver cancer (post-TACE)*

Nexavar (sorafenib)/

sunitinib

Adjuvant kidney cancer

Nexavar (sorafenib)

Adjuvant kidney cancer **

Nexavar (sorafenib)/

gemcitabine/

cisplatin

First-line non-small cell lung

cancer

Nexavar sorafenib)/

carboplatin/

paclitaxel

First-line melanoma

Approved

Nexavar (sorafenib)

Advanced kidney cancer

Nexavar (sorafenib)

First-line liver cancer

* Japan ** European Union

Chronic Lymphocytic Leukemia Treatment Approved: First New Option in Seven Years

In April, the FDA announced the approval of injectable Treanda (bendamustine hydrochloride). Manufactured by Cephalon, Inc., Frazer, Pennsylvania, the company obtained an indication for the first-line treatment of patients with chronic lymphocytic leukemia (CLL). The approval represents a welcome, long-awaited addition to the arsenal of available CLL therapies. In the United States, the last novel option for combating the disease was brought to market back in 2001.

Cephalon’s initial application to the FDA was submitted in September of 2007. The approval process was expedited because priority review status was granted. In addition to basic FDA approval, Treanda has obtained much-coveted orphan drug status. The orphan drug designation will provide marketing exclusivity in the CLL indication until 2015. A company spokesperson reported that the product will be accessible to physicians and patients by the time these words are published.

The FDA’s affirmative decision was largely based on data derived from a randomized, international, multicenter, open-label study of 301 treatment-naïve patients with CLL, in which patients who were treated with Treanda demonstrated better clinical outcomes than a comparative cohort that underwent a regimen of chlorambucil therapy. Specifically, Treanda patients had a significantly higher overall response rate (ORR) — 59% of patients responded to Treanda, compared with 26% of patients who responded to chlorambucil. Patients who received Treanda also had a higher complete response (CR) rate than those treated with chlorambucil (8% vs. less than 1%). Treanda patients also evidenced significantly longer progressionfree survival (18 mo vs. 6 mo) and duration of response (19 mo vs. 6 mo). The frequency of adverse event incidence in both arms of the trial was relatively limited. In general, when sideeffects and/ or adverse reactions were observed, they were neither serious nor severe.

Commenting on the significance of the approval from the perspective of both Cephalon’s clients and the company itself, Lesley Russell, MD, executive vice president, worldwide medical and regulatory operations, Cephalon, Inc. stated, “Treanda is an important new treatment for patients with CLL…This first-cycle approval by (the) FDA represents a significant milestone in the growth of our oncology business. With a strong pipeline of near- and longer-term opportunities, Cephalon Oncology is poised to deliver therapies that target both hematologic cancers and solid tumors for patients in need of new options.”

According to Bruce Cheson, MD, clinical professor of hematology and oncology, Georgetown University School of Medicine, Washington, DC, “Patients with CLL can often live normal lives for many years because of treatments that control the disease over the long-term. Treanda is an effective new option that offers a delay in disease progression, an important goal for patients with CLL.”

The American Cancer Society estimates that more than 15,000 new cases of CLL will be diagnosed in the United States this year.

Cephalon researchers strongly believe that the utility of Treanda is not confined to CLL. In December 2007, for example, Cephalon submitted a new drug application requesting approval of Treanda for the treatment of patients with indolent non-Hodgkin's lymphoma who have progressed during or following treatment with rituximab or a rituximab-containing regimen. The company anticipates an FDA review decision by October 31, 2008.

Currently, the Cephalon Oncology (a strategic subsidiary of Cephalon that is focused exclusively on cancer therapy—related research, development, commercialization, and care) portfolio includes a number of investigational and marketed compounds. In addition to Treanda, Cephalon Oncology products include Trisenox (arsenic trioxide) injection, a product approved in the United States for the treatment of patients with relapsed or refractory subacute promyelocytic leukemia; and CEP-701, an oral small molecule inhibitor of tyrosine kinases (including FLT-3, TRK, and JAK-2), currently in phase III development for acute myeloid leukemia. In Europe, Cephalon markets three additional oncology products in 19 countries.

Non-Hodgkin’s Lymphoma: New Challenges, New Hope

Non-Hodgkin’s lymphoma (NHL) has been perplexing scientific investigators and other oncology professionals for almost a generation now. For reasons that no one can understand, the incidence rates of the disease, which occurs when immune cells become malignant, has roughly doubled since the beginning of the 1980s.

Once relatively uncommon, NHL is now the fifth leading cause of cancer in the United States. Although the upward curve of new NHL cases has flattened out somewhat in recent years, the number of patients being diagnosed with the disease is still growing by between 1% and 2% each year.

The New York Times

Recent developments, however, offer a great deal of promise, suggesting that prospects will likely improve for NHL patients and that the vexing and troubling mystery of the disease may eventually be better understood. A recent article on NHL in quoted Issa Khouri, MD, University of Texas, MD Anderson Cancer Center, as stating, “the treatment of non-Hodgkin’s lymphoma has evolved significantly in the last seven or eight years. Many more patients are experiencing long-term remissions and even cures.”

Dr. Khouri’s assertions have the weight of raw data behind them: recent analysis of National Cancer Institute statistics shows that five-year survival rates for the disease have jumped from just over 50% in the early 1990s to almost 67% in 2004.

Part of the credit for the improved state of NHL treatment belongs to a class of therapies known as monoclonal antibodies. In 1997, the FDA approved Rituxan, the first monoclonal antibody—based cancer treatment for NHL. Used in combination with chemotherapy, Rituxan improves the odds of inducing long-lasting cancer remission. Many doctors now use the drug as a first-line treatment for indolent (a less aggressive form of) non-Hodgkin’s lymphoma.

More recently, two variations on Rituxan—Bexxar (tositumomab) and Zevalin ([90Y]-ibritumomab tiuxetan)— have joined the fight. Both are monoclonal antibodies armed with small radioactive particles, targeted to deliver radiation directly to NHL cells, an approach called radioimmunotherapy.

Sometimes monoclonal antibodies utilized in combination with nonablative stem-cell transplantation, a treatment technique that involves suppressing a patient’s immune system with low doses of chemotherapy, then introducing stem cells from a donor that detect and destroy lymphoma cells. Nonablative stem-cell transplantation requires only low doses of chemotherapy. Therefore, it can be used in elderly patients who can not tolerate high-dose chemotherapy. That presents a key advantage, since NHL usually strikes people in their 60s, and risk of the disease increases with age.

The variety of new treatment options have oncologists working overtime to figure out the most effective combination regimens, best dosage levels, and optimum drug delivery timing. To facilitate this process, almost 800 clinical trials are currently underway to evaluate potential NHL treatments and treatment combinations.

One of the more notable recent studies, (the prospective, single-arm, open-label, multicenter, non-randomized phase II FLUMIZ—Fludarabine, Mitoxantrone, Zevalin—trial, reported by P.L. Zinzani, et al, Institute of Hematology and Medical Oncology at the University of Bologna, Bologna Italy, conducted at 13 Italian institutions), examined Zevalin consolidation following sequential fludarabine and mitoxantrone therapy without rituximab in order to determine the tolerability and efficacy of the combination regimen in first-line treatment of follicular NHL. Sixty-one patients with advanced (stage III-IV) follicular NHL were treated with six cycles of fludarabine and mitoxantrone chemotherapy; Subsequently, 57 patients (43 with Complete Response CR and 14 with partial remission PR were treated with Zevalin therapy. Consolidation with Zevalin converted 12 of 14 PRs (86%) to CRs for a complete response rate of 96%. With a median follow-up of 30 months, estimated three-year progression-free survival (PFS) was 76% and estimated three-year overall survival was 100%. Twenty-two percent of patients tested (5 of 23) achieved a molecular remission following chemotherapy. Zevalin consolidation induced a molecular remission in 14 of 18 patients (78%) tested who did not achieve a molecular remission after fludarabine-mitoxantrone therapy. Grade 3 or higher thrombocytopenia, neutropenia, and anemia occurred in 63% (36 of 57), 53% (30 of 57), and 23% (13 of 57), respectively. Febrile neutropenia occurred in 9% (5 of 57) of patients. Patients who relapsed were treated with CHOP plus rituximab as salvage therapy and all tolerated six cycles of therapy, indicating that treatment with Zevalin did not preclude the ability to administer an aggressive salvage regimen.

“This study underscores the potential use of radioimmunotherapy with Zevalin to convert the majority of PRs to complete remissions and to induce molecular remissions after conventional chemotherapy, both of which correlate with durable PFS rates,” noted Jack W. Singer, MD, chief medical officer, Cell Therapeutics, Seattle.

The Lancet.

Results of the study were reported in a recent on-line edition of Cell Therapeutics acquired the U.S. rights to Zevalin in December, 2007.

Potential Ovarian Cancer Treatment Advancing Through Development Pipeline

Sunesis Pharmaceuticals, Inc., South San Francisco, California, recently reported that an ongoing phase II trial of its lead product candidate, SNS-595, has produced positive interim data. The agent, which is being evaluated as monotherapy in a population of patients with platinum-resistant ovarian cancer, has demonstrated disease control (defined herein as stable disease, partial response or complete response) in 31 of 35 patients who were evaluable for best response (GOG-RECIST criteria were employed to reach disease control determinations concerning trial participants).

Of the 31 patients who met the established disease control threshold, one patient had a complete response, four patients had partial responses (two unconfirmed) and 26 patients had a best response of stable disease. All patients enrolled in the trial have previously failed treatment with platinum-containing regimens. In addition, 14 of the 35 patients also failed prior treatment with doxorubicin HCl liposome injection (Doxil). Both platinum-resistant and doxorubicin-resistant patients responded to the SNS-595 therapy they have undergone throughout the course of the trial so far.

Among 45 patients who generated sufficient duration of participation to yield safety data, SNS-595 was generally well tolerated at a dose level of 48mg/m², administered once every three weeks. Adverse events were relatively mild, and, when they were not, were relatively rare. To date, the most common adverse events reported include nausea, fatigue, vomiting and alopecia. There was a low rate of febrile neutropenia or other grade 3 or higher adverse events, and manageable grade 1 and grade 2 nausea or vomiting.

Based on the indications of clinical activity and the acceptable tolerability profile demonstrated to date among this patient population, the dose of SNS-595 in this trial has been increased to 60 mg/m² over 28 days. Patient accrual at this dose level is ongoing.

The interim clinical results were being presented in a poster, “A Phase 2 Trial of SNS-595 in Women with Platinum-Refractory Epithelial Ovarian Cancer” (Abstract # 290), at the 39th Annual Meeting on Women's Cancer hosted by the Society of Gynecologic Oncologists in Tampa, Florida.

“We are pleased by the strong signal of activity emerging from our phase II clinical trial of SNS-595 at the 48mg/m² dose level. Based on the drug's observed safety profile and recommendations from advisors, we are exploring a higher dose of SNS-595 in this trial. Enrollment has begun at 60 mg/m² and we expect to enroll approximately 30 patients at this dose by the third quarter of this year. Enthusiasm for SNS-595 among our clinical investigators is growing and enrollment in this trial has been accelerating. We expect to present further data from this phase II clinical trial this year,” reported Daniel C. Adelman, MD, senior vice president, development and chief medical officer, Sunesis.

William P. McGuire, MD, medical director, Harry and Jeanette Weinberg Cancer Institute at Franklin Square, Baltimore, Maryland, and a lead investigator for the phase II trial, stated, “recurrence rates among ovarian cancer patients remain high, and the majority of refractory patients are resistant to platinum-based therapies. Based on these interim data, SNS-595 appears to be promising.

Enhanced Survival, Tolerability Observed in Joint Non-Small Cell Lung Cancer Trial

BioNumerik Pharmaceuticals, Inc. and ASKA Pharmaceutical, headquartered in San Antonio and Tokyo, respectively, have announced the results of a joint phase III clinical trial analyzing Tavocept, (an investigational new drug with a range of potential oncology applications), in a population of patients with advanced non—small cell lung cancer (NSCLC).

The multicenter, double-blind, randomized, placebo-controlled phase III clinical trial was conducted by KI Pharmaceuticals, Inc., a corporate vehicle based in Tokyo, Japan that was created to facilitate the joint venture of ASKA and BioNumerik. The KI Pharmaceuticals, partnership is aimed at developing a broad portfolio of new compounds for distribution in the Japanese market. KI Pharmaceuticals, Inc., holds the exclusive right to develop, market, distribute, and sell Tavocept (also known as BNP7787) in Japan. BioNumerik holds exclusive rights to Tavocept outside of Japan.

The study included 182 patients with advanced NSCLC who received the chemotherapy drugs paclitaxel and cisplatin as first-line therapy every three weeks. Half of all patients in the trial received Tavocept along with their chemotherapy, while the other half received a placebo and chemotherapy. The primary trial endpoint was to evaluate Tavocept's potential for preventing and reducing the severity of sporadic and cumulative nerve damage, or neuropathy, experienced by patients receiving paclitaxel and cisplatin chemotherapy.

The trial results indicated that the number of patients reporting either severe sporadic or cumulative neuropathy was approximately 50% lower in the Tavocept arm of the trial compared with the placebo arm. While this outcome represents a strong trend in favor of Tavocept, the results are not statistically significant. BioNumerik and ASKA believe the lack of statistical significance is likely caused by the relatively small size of the trial.

According to a spokesperson for the two pharmaceutical concerns, a “surprising” and “medically important” outcome of the trial was the increase observed in median survival time for patients receiving Tavocept when compared with those receiving placebo. The median survival time observed for patients receiving Tavocept was approximately 40 days longer than for patients receiving placebo. For patients with adenocarcinoma, the most frequently occurring type of lung cancer, the median survival time, compared with those receiving placebo, was increased by approximately 138 days for patients receiving Tavocept.

Additional observations from the trial included a statistically significant reduction in cisplatin-induced kidney damage (nephropathy) and a statistically significant reduction in chemotherapy-induced vomiting for patients receiving Tavocept in comparison withthose receiving placebo. There were also substantially fewer instances of physician chemotherapy dose reductions, treatment delays or discontinuance of chemotherapy treatment because of neuropathy in the Tavocept arm of the study, compared with the placebo arm. Patient quality-of-life questionnaire scores were more favorable in the Tavocept arm of the study. Furthermore, trial results included substantial evidence of the potential ability of Tavocept to maintain or stimulate hematological function in the body, as well as the potential to mitigate or prevent chemotherapy-induced anemia and to maintain or stimulate erythropoietin function or synthesis.

Frederick H. Hausheer, MD, chairman and chief executive officer, BioNumerik, and chairman, KI Pharmaceuticals, Inc., stated, “we are encouraged by the observed evidence of Tavocept's potential to protect against sporadic (i.e., intermittent) and cumulative chemotherapyinduced neuropathy. The observed survival benefit in this patient population along with significant reductions in renal toxicity, vomiting, and anemia further support our belief in this drug's therapeutic potential. We believe that this phase III trial outcome is an important step towards the validation of our approach to cancer drug discovery and development.” Hashime Kanazawa, PhD, executive director, ASKA, and president, KI Pharmaceuticals, Inc., commented, “We are pleased with this result, particularly the multiple statistically significant findings that were observed. These data will be the basis for further studies, which we intend to pursue expeditiously.”

Ross C. Donehower, MD, director of medical oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; professor of oncology and medicine at the Johns Hopkins University School of Medicine; and a member of BioNumerik's Scientific Advisory Board characterized the trial results as “very exciting,” adding that Tavocept “has the potential to improve cancer therapy and decrease toxicity in a meaningful way." Michael C. Perry, MD, professor of hematology and medical oncology, Ellis Fischel Cancer Center, University of Missouri- Columbia; and a member of BioNumerik's Scientific Advisory Board concurred, stating, “the findings of increased efficacy combined with decreased toxicity are very encouraging."