Niche-Disease: Amyloidosis

by Cheryl Scott

Amyloidosis is a family of rare diseases involving a build- up of misfolded (and thus insoluble) amyloid protein in one or more organs. The condition affects different organs in different people, involving different types of amyloid protein. It most frequently affects the heart, kidneys, liver, spleen, nervous system, and digestive tract. Severe amyloidosis can cause life-threatening organ failure, and there is no cure. Some 60 amyloid proteins have been identified, with about half of them associated with a form of the disease.

The three most common forms of this disease are amyloid light-chain (AL) amyloidosis; inflammatory amyloid A (AA); and transthyretin amyloidosis (ATTR), an inherited form caused by a mutation in the transthyretin (TTR) gene. Diagnosis typically comes later in life. In the United States, a few thousand new cases of AL amyloidosis are diagnosed each year. AA amyloidosis is the most common form in developing countries, where it can be complicated by tuberculosis, osteomyleitis, and bronchiectesis; in the developed world, it is more likely to occur alongside autoimmune disorders (e.g., rheumatoid arthritis, inflammatory bowel disease, and psoriasis). Senile amyloidosis involves deposition of normal transthyretin, mainly in the heart, and is ultimately a leading cause of death in very long-lived individuals (those who live past 100).

Amyloidosis treatment varies by disease type. Early stages of the AL form are currently treated with high- dose chemotherapy and steroids, followed in some cases by stem-cell transplantation. Not all patients are eligible for the latter option, however. AA symptoms can improve if the underlying condition is treated. Biologic agents such a tocilizumab and infliximab have been used to successfully reduce inflammation in AA amyloidosis. But for ATTR, liver transplant is usually the answer. Prognoses vary. Untreated AL amyloidosis patients may live only one to two years. AA outcomes depend on the underlying disease. After transplantation, ATTR patients can survive for over a decade.

The Amyloidosis Foundation (www.amyloidosis.org) is a nonprofit organization founded in 2007 when two related organizations merged: the Amyloidosis Research Foundation and the Amyloidosis Support Network. The group supports research through a grant program, works to raise awareness of the disease, and helps patients and their families. In 2016, it will present an International Symposium on Amyloidosis in Uppsala, Sweden.

A few treatments are currently in clinical testing at Tufts Medical Center in Boston, MA; the Boston University School of Medicine; Memorial Sloan-Kettering Cancer Center in New York, NY; and the Mayo Clinic in Rochester, MN. Companies involved include Celgene Corporation, Columbia University and Cephalon, Millennium Pharmaceuticals (Takeda’s oncology subsidiary), Onyx Pharmaceuticals, CORE Science Solutions, Criterium Inc., Onclave Therapeutics, and CT Development America. The few treatments currently in development are mostly small-molecule, highly potent chemotherapies.

Conference Alert: This month, Informa Life Sciences presents a new conference at the Park Plaza Victoria in London, UK. On Tuesday and Wednesday, 24–25 February 2015, “Development of Orphan Drugs” will connect orphan drug developers, payers, suppliers, and patient groups to help them accelerate product development together. Find more information online at www.informa- ls.com/orphandrugs.

2014 Drug and Biologic Approvals

The US FDA approved 41 new medicines in 2014 (a dramatic increase over 2013’s 27), second only to the all-time high of 53 approvals in 1996. Reuters reported in January that this is the highest level in 18 years. “After suffering a wave of patent losses on blockbuster products, which peaked two years ago,” wrote Ben Hirschler of Reuters London, “drug-makers are recovering their ability to bring new medicines to market and productivity is improving.” Almost 40% of those new drugs in 2014 were expensive drugs for rare diseases. And the European Medicines Agency (EMA) recommended the a record high number (17) of orphan- designated medicines for market authorization as well.

Hirschler also pointed out that initial public offerings in biotechnology hit a record high in 2014 as well, with many drug-industry mergers and acquisitions assisting a 34% increase in the Nasdaq Biotechnology Index and a 23% rise in the S&P 500 Health Care Index. “Some fund managers are starting to question valuations,” he cautioned, “as insurers take a tougher stance on prices.”

Addressing the Antimicrobial Agenda

The 2014 BioInfect conference took place at the Alderley Park Conference Centre, Cheshire on the 4th November 2014. Bionow — a not-for-profit membership organization for biomedical/life-sciences industry — declared the one-day meeting a success. Participants discussed developing innovations for tackling the increasing problem of antibiotic resistance while creating new antiinfective medications. Scientists, policy-makers, and government officials convened to set the antimicrobial agenda in three main sessions: “Progress: National and International Perspectives,” “Animal Health: The Issues,” and “Commercial Models.”

In addition, a company technology showcase presented leading innovations and developments in related areas. It included some of the latest innovations from companies in the United Kingdom’s northern region. A number of early stage, proprietary therapeutics are moving away from the broad-spectrum approach toward more focused methodologies somewhat akin to the targeted approach being taken with cancer. Products based on cutting-edge nanopolymer drug delivery technologies were an additional focus along with biologic and vaccine approaches to developing treatments to meet the high unmet medical needs of infectious disease.

BioInfect explored other research into technological tools for health workers to diagnose, manage, monitor, and track emerging infections and drug resistance. Participants discussed development of novel drugs for treating life-threatening fungal diseases. Such infections typically affect immune-compromised patients, for whom mortality rates can be very high. That patient population is increasing every year due to greater numbers of cancer cases and organ transplants, as well as the use of potent immune-modulating medicines.

Geoff Davison (Bionow’s chief executive officer) says, “We are very pleased with the attendance, engagement, and feedback received. Key areas that can move this agenda forward were discussed. BioInfect brings together professionals from the life-sciences industry, universities, the UK national health service (NHS), government, and policy-making bodies to explore areas that can truly address this problem for mankind. To tackle growing levels of antimicrobial resistance, we need to address this global problem in a truly coordinated way through open and coordinated discussion and planning to ensure that we have a healthcare system that can sustainably control and treat infections.”

Hosted by Bionow and Redx Pharma, BioInfect was supported by AstraZeneca and sponsored by HGF Ltd., Boyds, and Shore Capital. The 2015 conference is scheduled for Wednesday, 4 November 2015, at the Alderley Park Conference Centre in Cheshire, UK. Find more information online at www.bionow.co.uk.

Public Company? Beware of Cyberattacks! 

Late in 2014, security firm FireEye reported a hacking threat of particular note to the biopharmaceutical industry. Since mid-2013, the FIN4 group has targeted more than 100 publicly traded companies and advisory firms that provide investor, legal, and financial services. Some 68% of targets are involved in healthcare and drug development, fully half of those in biotechnology.

FIN4 knows its targets. “Spearphishing” attempts appear to be written by native English speakers who are familiar with investment terminology and the inner workings of public companies. The scheme does not infect victims with malware, but rather focuses on capturing usernames and passwords that allow FIN4 to view private email correspondence. So-called phishing lures are sent from other victims’ email accounts and hijacked email threads. “These lures appeal to common investor and shareholder concerns,” says FireEye, “enticing intended victims into opening a weaponized document and entering their email credentials.” FIN4 often targets several parties involved in a single business deal, evidence of the group’s organization of collected data. And it has taken steps to evade detection.

What should arouse your suspicions? According to the report, “FIN4’s phishing emails frequently play up shareholder and public disclosure concerns.” For example, one email describes an employee making negative comments about a company and its leadership on public investment forums. The “weaponized” emails are designed to be very difficult to distinguish from legitimate business correspondence. FIN4 has even used false “Windows Security” pop-ups to collect user credentials: e.g., “Your Outlook session has expired. Please log in to continue.”

FireEye says that the hackers probably use their inside information to capitalize on stock fluctuations. Bloomberg reports that the US FBI is investigating, but the problem is ongoing. Download this free report for more information and suggestions on protecting your company’s information: https://www.fireeye.com/content/dam/ fireeye-www/global/en/current-threats/pdfs/rpt-fin4.pdf.

CORRECTION: November 2014 Issue

References 64–67 (cited in Table 3) are not included in the list of at the end of “Immunoglobulin Fc-Fusion Proteins, Part 2: Therapeutic Uses and Clinical Development” by Angela L. Linderholm and Steven M. Chamow on pages 20–27 of BPI’s November 2014 issue. The missing references are as follows:

64 Jimenez-Solem E, et al. Dulaglutide, a Long-Acting GLP-1 Analog Fused with an Fc Antibody Fragment for the Potential Treatment of Type 2 Diabetes. Curr. Opin. Molec. Therapeut. 12, 2010: 790–797.

65 Bouman-Thio E, et al. A Phase I, Single and Fractionated, Ascending-Dose Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of an Erythropoietin Mimetic Antibody Fusion Protein (CNTO 528) in Healthy Male Subjects. J. Clin. Pharmacol. 48, 2008: 1197–1207.

66 Achuthanandam R, et al. Pharmacodynamics of CNTO 530 and Darbepoetin Alpha in Human TNF Alpha Transgenic Mice, a Murine Model of Anemia of Chronic Disease. Pharmacol. Pharmacy 2(2) 2011: 17–30.

67 Hartmann N, et al. Recombinant CD95-Fc (APG101) Prevents Graft-Versus-Host Disease in Mice Without Disabling Antitumor Cytotoxicity and T-Cell Functions. Blood 121, 2013: 556–565.