Nuvelo

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Nuvelo Inc. was a biopharmaceutical company engaged in the discovery, development and commercialization of drugs for acute cardiovascular disease, cancer and other debilitating medical conditions. On January 27, 2009, the company was acquired by ARCA Biopharma, Inc. in a reverse takeover transaction.

A biopharmaceutical, also known as a biologic(al) medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, they include vaccines, blood, blood components, allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein, and living cells used in cell therapy. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living cells or tissues. They are isolated from living sources—human, animal, plant, fungal, or microbial.

Cardiovascular disease class of diseases that involve the heart or blood vessels

Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction. Other CVDs include stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

Cancer disease of uncontrolled, unregulated and abnormal cell growth

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they can also have other causes. Over 100 types of cancers affect humans.

Contents

The company

Nuvelo, Inc. was located at San Carlos, California and had approximately 250 employees. Corporate officers included chairman George Rathmann (founder and CEO of Amgen), CEO Ted Love, and executive vice president Michael Levy. The company's development pipeline included:

San Carlos, California City in California, United States

San Carlos is a city in San Mateo County, California on the San Francisco Peninsula, about halfway between San Francisco and San Jose. It is a small residential suburb located between Belmont (north) and Redwood City (south). The population is 28,406 per the 2010 census.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis. The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

Thrombosis vascular disease caused by the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

Thrombin mammalian protein found in Homo sapiens

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

In addition, Nuvelo had research programs in leukemia therapeutic antibodies and Wnt signaling pathway therapeutics to expand its drug pipeline and create additional partnering and licensing opportunities. [4]

Leukemia group of cancers that usually begin in the bone marrow

Leukemia, also spelled leukaemia, is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, feeling tired, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

Antibody large Y-shaped protein produced by B-cells, used by the immune system; large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly. Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region, which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the name Wingless and the name Int-1.

Start-up phase and core competency

Nuvelo was initially founded as Hyseq in August 1992 and based on DNA array technology. Hyseq's genomic platform was used to develop gene based therapeutics and diagnostics. At the rate of more than 1,000,000 human DNA samples analyzed per month during 1997, Hyseq was a large partial human gene sequence database with over 5,000,000 sequences. The HyX platform had five core technologies:

DNA microarray

A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome. Each DNA spot contains picomoles of a specific DNA sequence, known as probes. These can be a short section of a gene or other DNA element that are used to hybridize a cDNA or cRNA sample under high-stringency conditions. Probe-target hybridization is usually detected and quantified by detection of fluorophore-, silver-, or chemiluminescence-labeled targets to determine relative abundance of nucleic acid sequences in the target. The original nucleic acid arrays were macro arrays approximately 9 cm × 12 cm and the first computerized image based analysis was published in 1981. It was invented by Patrick O. Brown.

Genome entirety of an organisms hereditary information; genome of organism (encoded by the genomic DNA) is the (biological) information of heredity which is passed from one generation of organism to the next; is transcribed to produce various RNAs

In the fields of molecular biology and genetics, a genome is the genetic material of an organism. It consists of DNA. The genome includes both the genes and the noncoding DNA, as well as mitochondrial DNA and chloroplast DNA. The study of the genome is called genomics.

Gene therapy therapeutic approach that involves inserting nucleic acids into the patients cells

In the medicine field gene therapy is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease. The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Transition towards therapeutics

Applications that were developed making use of the genomic platform included gene identification, expression analysis, polymorphism screening and diagnostic testing. The company strategy was to exploit this platform technology to enter gene discovery and to eventually produce therapeutic drugs.

This technology led to collaborations and partnerships with companies and academic institutions including Affymetrix, PerkinElmer, Aurora biosciences, Amgen, Genetastix, Agilent Technologies, Callida Genomics, Aspen Institute, University of California, San Francisco, Celera Diagnostics, Surromed, Variagenics, Sequenom, Archemix, Amgen and Bayer. The company also created revenue by out-licensing their technologies with other companies.

Partnerships

In the early days of Nuvelo, when they were called Hyseq, there was a great deal of partnering activity. This was due to their business model which centered on their high-throughput sequencing platform. The company simply partnered or licensed out any novel discovery that did not fall into their desired disease space. Listed below are some of the material collaborations that the company undertook.

Dendreon

Nuvelo obtained the worldwide rights for all indication of rNAPc2 and other rNAPc molecules owned by Dendreon Corporation. Dendreon was paid an upfront fee of $4.0 million with an additional $23.5 million if all development and commercialization milestones are achieved. In addition, royalty payments were structured.

Amgen

In October 2004, Nuvelo obtained the worldwide rights to develop and commercialize alfimeprase from Amgen in exchange for future payment to Amgen as negotiated under their initial deal.

Archemix

In January 2004, the company signed a 50/50 agreement with Archemix. In July 2006, the collaboration was expanded in that Archemix became responsible for the discovery of short-acting aptamers targeting coagulation cascade for use in acute cardiovascular procedures. Nuvelo was responsible for the development and commercialization of any products discovered.

Bayer

January 2006, Nuvelo partnered to develop Alfimeprase. Bayer was to commercialize the drug outside the United States. Nuvelo retained commercial rights in the United States market and was to receive ROW royalties ranging from 15% to 37.5%. The deal was structured with a $50 million upfront payment and milestone payments totaling $385 million ($165M in development milestones and $170M in sales and commercialization). Although many of these milestones were never achieved, in 2006 a total of $28.9M was billed to Bayer under their cost-sharing agreement.

In February 2003, Hyseq merged with Variagenics giving birth to “Nuvelo Inc.” to further development of drug “alfimeprase.” This drug therapy was developed against peripheral arterial occlusion or “Leg Attack” disease and was approved as orphan drug status. This accelerated the clinical development of alfimeprase.

Merger

Early stage clinical trials for alfimeprase with NU206 (R-respondin protein) and NU172 (short acting thrombin inhibitor) were promising and were approved by the FDA. Bayer was collaborating with Nuvelo on late stage studies on alfimeprase. After Nuvelo's failure in these studies, Bayer closed the deal in June 2007. However, Nuvelo was optimistic and continued the trial with alfimeprase. However, in March 2008, Nuvelo's phase II trial failed to meet endpoints, thereby forcing Nuvelo to discontinue the trial. The company laid off forty employees and restructured the organization. Also, executive vice president Michael Levy left the company

Nuvelo's market cap reached a peak of approximately $US 1 billion in the lead up to alfimeprase phase 3 studies completion, but share price plummeted eventually to less than $1 and received notification from NASDAQ. Despite this, Nuvelo was able to show positive proof of concept for NU172 in August 2008. Following this, Nuvelo was merged with ARCA Biopharma Inc. on September 26, 2008 forming a late stage cardiovascular biotechnology company. ARCA biopharma focuses on developing genetically targeted cardiovascular therapies, with lead candidate drug Gencaro, a beta blocker and vaso-dilator. It was Nuvelo's genetically targeted technology and cardiovascular drug development that interested ARCA Biopharma in acquiring the company.

According to the merger agreement, Nuvelo issued new shares of its common stock to ARCA stockholders and assumed the outstanding options and warrants involved. Novelo CEO Ted Love took a seat on the board of the combined business and Arca CEO Richard Brewer became CEO of the new business. The option and warrant holders were expected to own 67% of the combined company's common stock and Nuvelo stockholders 33% of the new company.

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