Nuvelo, Inc., a biopharmaceutical company, engages in the discovery, development, and commercialization of drugs for acute cardiovascular and cancer therapy. Its leading pipeline candidate is alfimeprase, a direct-acting thrombolytic that is in phase III clinical trials for the treatment of thrombotic-related disorders. In addition, the company is developing NU206 for the treatment of chemotherapy/radiation therapy-induced mucositis and irritable bowel disease, as well as NU176 for thrombin inhibitor for potential use as an anticoagulant in medical or surgical procedures. The company has strategic alliances with Amgen, Inc., Dendreon Corporation, Kirin Brewery Co., Ltd., and Archemix Corporation. Nuvelo was founded in 1991 and is headquartered in San Carlos, California.
In early August 2007, Nuvelo announced that it was reducing its workforce by approximately 30% and realigning its organization to focus on core development programs that it believes will produce nearest-term proof-of- concept data. This included suspending all development programs for rNAP2c in both cardiovascular disease and oncology, and moving forward with development of alfimeprase, NU206 and NU172. As a result of the reduction in workforce the company expects to have less than 80 employees, a reduction of 45% from year end 2006. Nuvelo expects this realignment of personnel and programs to result in reduced annual expenses of approximately $15 million from current levels. Also, as part of the reorganization, Ward Wolff, CFO, will be leaving the company. Severance and career transition assistance to the employees directly affected by the restructuring will result in a $2.5 million charge in the third quarter of 2007.
Alfimeprase is a recombinant novel thrombolytic agent (blood clot dissolver) that directly degrades fibrin when delivered through a catheter at the site of the blood clot. The product is a truncated form of fibrolase, a fibrinolytic agent common in snake venom. Fibrin is an elastic, insoluble, whitish protein derived from fibrinogen that provides the scaffolding for blood clots. Alfimeprase, when delivered through a catheter, degrades this fibrin network that causes blood to clot. Once the alfimeprase is free from the blocked area, it is rapidly inactivated by alpha-2-macroglobulin, a naturally occurring protein in the blood. This localized delivery and subsequent activity of alfimeprase greatly reduces the risk of dangerous bleeding side effects. On December 11, 2006 management reported that both the NAPA-2 and SONOMA-2 trials failed to meet their respective its primary endpoints. This was shocking news considering the previous positive phase II data.
Peripheral Arterial Occlusion (PAO), also known as "leg attack", occurs when a blood clot blocks arterial flow to a leg. Nuvelo estimates that more than 100,000 people in the U.S. each year develop PAO. Over time PAO can develop into peripheral arterial disease the chronic fatty plaque buildup within the artery. If left untreated, PAO can lead to permanent nerve and muscle damage and gangrene. The most severe cases can result in leg amputation or death. There are currently no approved therapies in the U.S. to treat acute PAO. For this the U.S. FDA granted Alfimeprase "Orphan Drug" status and Fast Track development designation.
Physcians will typically treat acute PAO with off-label use of tissue plasminogen activators (tPA) such as Genentech's Activase (alteplase) or TNKase (tenecteplase). However, both these products increase the risk of downstream bleeding, including intracranial bleeding. These products have also been known to increase the risk of hemorrhagic conversion in ischemic stroke patients. Plasminogen activators may require a prolonged infusion averaging 24 to 36 hours in patients with acute PAO and typically require the patient to be admitted into the intensive care unit (ICU) for the duration of the infusion. This is because tPA is uses and indirect method along the blood cascade to degrade fibrin. The activity of the drug is dependent on the level of plasminogen present at the clot. Nuvelo was developing Alfimeprase as a superior option based on a number of levels. Firstly, the direct fibrin degradation is not quantity specific, allowing Alfimeprase to dissolve clots in as little as four hours. Secondly, because of this increased activity, patients can avoid a lengthy and expensive ICU stay. And finally, clinical studies have demonstrated significantly lower bleed risk with Alfimeprase. This reduces the risk of intracranial bleeding or hemorrhagic conversion.
A previous phase II trial dubbed NAPA-1(Novel Arterial Perfusion with Alfimeprase 1) in acute PAO completed June 2004 with data presented at the Transcatheter Cardiovascular Therapeutics Scientific Symposium in September 2004. The drug demonstrated a 76% improvement in thrombolysis (clot busting) and a 60% improvement in arterial flow within four hours of initiation of the dose. Additionally, up to 69% of study patients were able to avoid open vascular surgical intervention in the 30 days following treatment with Alfimeprase. Among the 113 patients enrolled in the phase II study, there were no intracerebral hemorrhages or deaths at 30 days.
Based on these positive phase II data, Nuvelo progressed with two phase III trials designated NAPA-2 and NAPA-3. NAPA-2 (n=300) completed enrollment in early September 2006 and offered data on December 11, 2006. The trial was 90% powered to show a 21% absolute benefit vs. placebo in avoidance of open vascular surgery within 30 days of treatment. Unfortunately, there was no statistical difference between alfimeprase and placebo in avoidance of open vascular surgery (OVS). This was a direct contradiction to the phase II results discussed above. According to management, there was an abnormally high placebo effect (less patients progressing to OVS) combined with poor alfimeprase results (less avoidance than expected based on phase II outcomes). What was equally shocking was that key secondary measures such as bleeding incidence and pharmaco-economic endpoints were also missed. Management has closed the NAPA-3 program and plans no future clinical work in PAO for the near-term.
Catheter occlusion (CO) is the blockage of flow through a central venous catheter obstructed by a clot. Nuvelo estimates that about 5 million catheters are placed in patients each year in the U.S., of which approximately 25% become occluded. Current treatment for CO includes invasive surgery to remove and replace the catheter or treatment with Genentech's Cathflo-Activase. Management estimates the market opportunity in the U.S. for a superior product could be $100 million. A phase II trial called SONOMA-1 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase 1) on 55 patients was completed in July 2004. Nuvelo presented data at the December 2004 American Society of Hematology (ASH) demonstrating the ability of Alfimeprase to lyse clots in as early as five minutes. Alfimeprase restored flow to 40% and 50% of clotted catheters 5 and 15 minutes after the first dose, respectively, while Cathflo-Activase restored flow to 0% of catheters after either time point. In addition, alfimeprase restored flow to 60% of occluded catheters at 120 minutes after the first dose and to 80% of occluded catheters at 120 minutes after the second dose compared with 46% at 120 minutes after the first dose and 62% at 120 minutes after the second dose with Cathflo-Activase.
Based on this positive phase II trial, Nuvelo progressed with two phase III programs designated SONOMA-2 and SONOMA-3. SONOMA-2 (n=303) completed enrollment in early September 2006 and offered top-line data in December 2006. At that time all we knew was the statistical significance at 15 minutes was p=0.022, shy of the pre-determined p=0.00125 necessary for a single trial approval. The full results were presented just recently at the December 2007 ASH meeting. The data showed that alfimeprase resorted catheter function in 34.3% of the patients at 15 minutes vs. only 21.6% on placebo (p=0.022). However, we do note that statistical significance improved at the 30 minute market, with alfimeprase restoring 52.7% vs. 30.4% for the placebo (p=0.0002). Both adverse events (65.8% vs. 59.4%) and serious adverse events (15.5% vs. 16.8%) were similar between the two arms, including hemorrhagic events at 3.6% vs. 10.9%.
As noted back in December 2006, the p=0.022 significance with respect to restoration of catheter function fell short of the predetermined p=0.00125 endpoint necessary to gain marketing approval based on a single pivotal trial. Because the trial fell short of the p=0.00125 hurdle, management can conduct an additional similar trial with a hurdle of p=0.05. In fact, this program, called SONOMA-3, was initiated in August 2007. The trial will focus on a higher dose of 10mg and 5mg/mL concentrations in roughly 100 patients. This will be an open label trial and we expect enrollment will proceed quickly with data in the second quarter of 2008. If the SONOMA-3 trial can show repeat efficacy at the p=0.05 level there may ultimately still be a path to market in CO.
Continuing with alfimeprase, management plans to conduct a phase II proof-of-concept trial on roughly 100 patients at 40 sites in the U.S. with acute ischemic stroke in a study called CARNEOS-1 (Catheter directed Alfimeprase for Restoration of Neurologic function and Rapid Opening of arteries in Stroke). The key primary endpoints of the trial focus on safety and avoidance of hemorrhagic transformation. However, the trial will also be able to show insight into angiographic clearing of the thrombus and restoration of blood flow to the affected part of the brain. Management will also analyze clinical outcomes as secondary endpoints, but statistical power will be low due to the small number of patients and short length of the time. What Nuvelo is trying to accomplish here is get some proof-of-concept data available and then present to Bayer or other potential partners for a larger-scale program.
Ischemic stroke accounts for 85% of the roughly 1.2 million stroke cases annually in the U.S. and Europe each year. Alfimeprase could be administered at the site of the stroke three to nine hours after the onset to bust the clot. The significantly reduced risk of hemorrhagic conversion could make the drug a superior alternative to heparin or urokinase clot dissolvers. Stroke is an enormous opportunity well beyond CO, so Nuvelo would need a commercialization partner if CARNEROS pans out. We remind investors that Bayer terminated its collaboration agreement with Nuvelo in PAO and CO in June 2007. However, the company does have a one time option to reacquire the Ex-U.S. rights to alfimeprase for $15 million based on pivotal stroke data.
Nuvelo previously had plans for a phase II program for Alfimeprase in DVT (deep vein thrombosis) in 2007 but this has been put on hold given the NAPA-2 and SONOMA-2 failures.
Early-Stage Looks Promising
Nuvelo has two early-stage candidates it is working on. The first, NU206, is an R-spondin-1 protein that is a potent stimulator of epithelial cells found in the upper and lower gastrointestinal (GI) track. The mechanism of action for NU206, Wnt pathway modulation, was published in the Proceedings of the National Academy of Sciences in September 2007. The candidate is the result of collaboration with Japan's Kirin Brewery. The company presented preclinical data at the 2007 American Association for Cancer Research meeting and published data in the April 2007 issue of Gastroenterology demonstrating that NU206 was able to decrease the severity of chronic colitis by restoring the epithelial lining and alleviating inflammation of the small intestine and colon. Nuvelo recently received U.S. FDA for clearance to move the program forward into phase I clinical trials. This trial is expected to start during the first half of 2008. NU206 could offer potential in a number of GI indications including chemotherapy and radiation therapy induced oral mucositis and irritable bowel disease (IBD).
According to the National Cancer Institute, mucositis occurs when cancer treatments break down the epithelial cells lining the GI tract leaving the tissue open to ulceration and infection. It is one of the most common complication chemo and radiation therapies. As high as 35% of patients treated with chemotherapy, and 50% of patients receiving both chemo and radiation therapy, can develop mucositis. Left untreated, mucositis can lead to hypovolemia, electrolyte abnormalities, and malnutrition. The current market leader is Amgen's Kepivance. Inflammatory bowel disease (IBD) is principally treated by anti-inflammatory agents such as corticosteroids or TNF-blockers. Management believes that NU206 has the potential to be work in combination with these other agents and cause the re-growth of normal gut epithelium and speed healing.
On August 1, 2006 Nuvelo and privately held Archemix Corp. expanded previous research collaboration for the development of short-acting aptamers targeting the coagulation cascade for use in acute cardiovascular procedures. Aptamers are single-stranded nucleic acids that form well-defined three-dimensional shapes, allowing them to bind target molecules in a manner that is conceptually similar to antibodies. Aptamers combine the optimal characteristics of small molecules and antibodies, including high specificity and affinity, chemical stability, low toxicity and immunogenicity and the ability to target protein-protein interactions. In contrast to monoclonal antibodies, aptamers are chemically synthesized rather than biologically expressed, offering a significant manufacturing and production advantages.
One such aptamer under development is NU172. The candidate is a short-acting direct thrombin inhibitor for potential use as an anticoagulant for patients undergoing medical or surgical procedures. Management is excited about the prospects for this drug candidate because animal model suggest that NU172 maybe a prudent anticoagulant that offers the potential for predictable anticoagulant effects, rapid onset and offset of action, reduce bleeding complications, and no risk of heparin-induced thrombocytopenia. NU172 is currently being evaluated in R&D enabling studies and Nuvelo expect to initiate a phase I trial of NU172 in early 2008. In the meantime, Nuvelo continues work with Archemix to discover other such candidates.
rNAPc2 on the Shelf
Recombinant nematode anticoagulant protein c2 (rNAPc2) is a recombinant version of a naturally occurring protein that has anticoagulant properties. The candidate blocks factor VIIa/tissue factor protease complex, which is responsible for the initiation of blood clot formation. Factor VIIa/TF is the first step in the coagulation cascade that eventually leads to the formation of thrombin and the fibrin protein scaffolding. The advantage of targeting the cascade at the beginning of the sequence is inhibiting the process before it even starts. This is unlike aspirin, heparins, and antiplatelet agents that target more downstream.
Nuvelo was previously developing rNAPc2 in two large indications: acute coronary syndromes (ACS) and metastatic colorectal cancer (mCRC). However, both indications would require large outcome-based trials and significant R&D dollars. These are also highly competitive areas and the hurdle rate for a superior product would be difficult for Nuvelo to achieve. Management has suspended development of rNAP2c in an effort to focus its resources on alfimeprase, NU206 and NU172. The company could return to rNAP2c at a later date. We were previously optimistic on rNAP2c, but understand limited resources and a highly competitive market for both indications make other candidates more prudent for Nuvelo at this time.