Compassionate Treatment Research Articles

2630. Treatment of RSV Lower Respiratory Tract Infection in Two Immunocompromised Children with Polyclonal Immunoglobulin Containing Standardized Levels of Neutralizing Anti-RSV Antibody

BackgroundRespiratory syncytial virus (RSV) can cause severe lower respiratory tract infection (LRTI) in immunocompromised children. There is no standard effective treatment, though ribavirin (inhaled or oral), pooled human intravenous immunoglobulin (IVIG), and monoclonal anti-RSV antibody (palivizumab) have been described. RI-002 (ADMA Biologics Inc.) is a pooled human polyclonal IVIG that contains standardized levels of neutralizing anti-RSV antibodies. It was recently FDA-approved for prophylaxis in primary immunodeficiency patients and has been used as compassionate treatment for RSV LRTI in stem cell transplant patients.MethodsTwo children with T-cell lymphoblastic lymphoma, both undergoing delayed intensification chemotherapy, were diagnosed with RSV LRTI. They were both treated with RI-002 under an emergency FDA Investigational New Drug protocol.ResultsPatient 1, a 4-year-old boy, was admitted with fever, neutropenia and nasal congestion, and diagnosed with RSV infection on hospital day (HD) 5. On HD17, he was intubated for respiratory failure. IVIG, palivizumab, and daily oral ribavirin were administered. On HD18, he required high frequency oscillator ventilation, nitric oxide, and paralysis. He was given RI-002 (1.5 g/kg on HD20 and 0.75 g/kg on HD22). He was placed on veno-venous extracorporeal membrane oxygenation (ECMO) on HD23. RSV PCR crossing point (Cp) values trended higher, but remained positive (table). On HD33, RI-002 was re-dosed (0.75 g/kg). Pulmonary compliance and chest CTs improved (figure). On HD52, ECMO support was discontinued. He was discharged on HD88, and currently requires no respiratory support. Patient 2, a 5-year-old boy, was admitted with fever, neutropenia, nasal congestion, cough, and stridor and diagnosed with RSV infection (HD1). He required nasal cannula oxygen. IVIG and daily oral ribavirin were administered. He was given RI-002 (1.5 g/kg on HD3 and 0.75 g/kg on HD5). By HD5, he was afebrile; oxygen was discontinued. He was discharged HD6.ConclusionHuman polyclonal IVIG containing standardized levels of neutralizing anti-RSV antibodies may be useful in the treatment of RSV LRTI in immunocompromised children. Future studies on the role of RI-002 in treatment of RSV infection in immunocompromised children are warranted. Disclosures All authors: No reported disclosures.

Immunoglobulin Treatment in Severe Ovarian Hyperstimulation Syndrome.

A 32-year-old woman undergoing an in vitro fertilization program was admitted to our hospital with the diagnosis of severe ovarian hyperstimulation syndrome (OHSS). Transvaginal ultrasonography showed two gestational sacs. Treatment with fluid restriction, serum albumin and intravenous furosemide was started, and repeated thoracentesis and paracenteses were performed. In the absence of clinical improvement, the patient was transferred to the intensive care unit and a therapeutic abortion was suggested. Due to the similarities between OHSS and idiopathic systemic capillary leak syndrome, we offered the patient compassionate treatment with intravenous immunoglobulins. After administration, the patient showed rapid improvement and we were able to suspend intravenous furosemide and serum albumin. She was discharged, and pregnancy has continued normally to date.LEARNING POINTSOHSS is an infrequent yet serious complication of assisted reproductive treatment that involves increased capillary permeability.In severe refractory cases, immunoglobulins may be a useful and safe treatment to reverse this syndrome.

The paradox of American evangelical views on immigration: A review of the empirical research

In view of the current crisis and controversies related to immigration, this article examines views of American evangelicals on the subject. Statements issued by national evangelical leaders and organizations generally call for immigration reform balancing concerns for law and order and border security with a call for the compassionate treatment of immigrants and creation of pathways to citizenship. But a survey of the numerous empirical studies on grassroots evangelical views on immigration reveals several paradoxes. Not only are the opinions of average evangelicals on immigration more restrictive than those expressed in the aforementioned statements, but their attitudes and the manner in which they form their opinions appear inconsistent with evangelical convictions. Compared to all other religious groups, white evangelicals have the most negative views regarding immigration. Underlying factors include the failure of evangelical churches to address the topic of immigration, a separation of personal ethics from views on public policy, lack of interaction between evangelicals and immigrants, Christian nationalism, and other social influences.

Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation

Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation

Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.

Global View of HIV Prevalence in Prisons: A Systematic Review and Meta-Analysis

We aimed to estimate the global prevalence of HIV, as well as cross-countries comparison in people who are in prison. We systematically assessed published studies reporting HIV prevalence among prisoners in the world. We searched international datasets banks, including PubMed, SCOPUS, Cumulative Index to Nursing and ISI web of science along with local databases and included original articles reporting data on the prevalence of HIV from 1980 to 2017. We included 72 studies that reported HIV prevalence for 2,275,930 adult male and female prisoners. The pooled estimate of HIV prevalence was 3.4% (95% CI 3.2%-3.6%); however, the prevalence of HIV across individual studies varied considerably (ranging from 0 in Bosnia and Herzegovina to More than 20% in Iran, Zambia, Spain) and statistical heterogeneity was substantial (I2=0.99, Q=121; P<0.0001). The prevalence of HIV among prisoners in the continents Asia, Africa, North America and Europe was estimated as 3.0% (95% CI 3.3%-4.3 %), 6% (95% CI -0.0%-2.0%), 4% (95% CI 3.0%-4.0%), 5.0% (95% CI 0.0%-11%), respectively. Protecting prisoners' health protects general public health. Successful HIV preventive measures in prisons include provision of HIV education and information; clean needles and syringes; drug treatment; and condoms. Governments have a moral and ethical obligation to prevent the spread of HIV/AIDS in prisons and to provide compassionate care, treatment and support for those infected.

Current State of Compassionate Phage Therapy.

There is a current unmet medical need for the treatment of antibiotic-resistant infections, and in the absence of approved alternatives, some clinicians are turning to empirical ones, such as phage therapy, for compassionate treatment. Phage therapy is ideal for compassionate use due to its long-standing historical use and publications, apparent lack of adverse effects, and solid support by fundamental research. Increased media coverage and peer-reviewed articles have given rise to a more widespread familiarity with its therapeutic potential. However, compassionate phage therapy (cPT) remains limited to a small number of experimental treatment centers or associated with individual physicians and researchers. It is possible, with the creation of guidelines and a greater central coordination, that cPT could reach more of those in need, starting by increasing the availability of phages. Subsequent steps, particularly production and purification, are difficult to scale, and treatment paradigms stand highly variable between cases, or are frequently not reported. This article serves both to synopsize cPT publications to date and to discuss currently available phage sources for cPT. As the antibiotic resistance crisis continues to grow and the future of phage therapy clinical trials remains undetermined, cPT represents a possibility for bridging the gap between current treatment failures and future approved alternatives. Streamlining the process of cPT will help to ensure high quality, therapeutically-beneficial, and safe treatment.

Cure of recurring Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae septic shock episodes due to complicated soft tissue infection using a ceftazidime and avibactam-based regimen: a case report

BackgroundInfections caused by multidrug-resistant Enterobacteriaceae are hard to treat and life-threatening due to reduced therapeutic options. Systemic infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains have increased in many European regions, becoming frequent in many clinical settings, and are associated with high mortality. The co-formulation of ceftazidime, a third-generation cephalosporin, with avibactam, a new suicide inhibitor beta-lactamase inhibitor able to block most Klebsiella pneumoniae carbapenemases, has been recently licensed, with promising results in patients with limited or absent therapeutic options. Little is known, however, as to the efficacy of such a combination in patients with soft tissue infections caused by multidrug-resistant Klebsiella pneumoniae carbapenemase-producing strains of Klebsiella pneumoniae.Case presentationA Caucasian 53-year-old man with paraplegia suffered multiple vertebral fractures due to a car crash. He was treated with external fixators that became infected early after insertion and were repeatedly and inefficiently treated with multiple antibiotics. He suffered repeated septic episodes caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains with a multidrug-resistant profile. Meropenem, tigecycline, and colistin combinations allowed only temporary improvements, but septic shock episodes recurred, in spite of removal of infected external fixators. After approval of pre-marketing prescription by our local Ethics Committee, full clinical resolution was obtained with a compassionate treatment using meropenem and ceftazidime/avibactam in combination for 16 days.ConclusionsOur experience provides additional evidence that ceftazidime/avibactam, possibly in combination with meropenem rescued by avibactam, may be an efficacious treatment option also for complicated skin and soft tissue infections caused by multidrug-resistant strains of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae.

Clinical Indications and Compassionate Use of Phage Therapy: Personal Experience and Literature Review with a Focus on Osteoarticular Infections.

The history of phage therapy started with its first clinical application in 1919 and continues its development to this day. Phages continue to lack any market approval in Western medicine as a recognized drug, but are increasingly used as an experimental therapy for the compassionate treatment of patients experiencing antibiotic failure. The few formal experimental phage clinical trials that have been completed to date have produced inconclusive results on the efficacy of phage therapy, which contradicts the many successful treatment outcomes observed in historical accounts and recent individual case reports. It would therefore be wise to identify why such a discordance exists between trials and compassionate use in order to better develop future phage treatment and clinical applications. The multitude of observations reported over the years in the literature constitutes an invaluable experience, and we add to this by presenting a number of cases of patients treated compassionately with phages throughout the past decade with a focus on osteoarticular infections. Additionally, an abundance of scientific literature into phage-related areas is transforming our knowledge base, creating a greater understanding that should be applied for future clinical applications. Due to the increasing number of treatment failures anticipatedfrom the perspective of a possible post-antibiotic era, we believe that the introduction of bacteriophages into the therapeutic arsenal seems a scientifically sound and eminently practicable consideration today as a substitute or adjuvant to antibiotic therapy.

Efficacy and safety of a novel nitric oxide generator for the treatment of neonatal pulmonary hypertension: Experimental and clinical studies

Persistent pulmonary hypertension of the newborn (PPHN) is a complex pathology resulting from a failure of the post-natal reduction in pulmonary vascular resistance leading to hypoxemia. The standard therapy is inhaled Nitric Oxide (NO) improving oxygenation but its availability is limited, especially in hospitals with restricted financial resources. We evaluated the efficacy and safety of a new device generating NO (TAS + PLUS), in three experimental piglet models of pulmonary hypertension (PH), and we later tested its application in a pilot study of newborn patients suffering from PPHN.Piglets with experimentally induced PH showed a decrease in pulmonary arterial pressure (PAP) after breathing NO. Both acute and chronic exposure of piglets and rats did not cause any adverse effect in blood gas levels and biological parameters. A pilot study including 32 patients suffering from PPHN showed an increase in oxygen saturation (SatO2) and partial pressure of oxygen in arterial blood (PaO2) leading to a decrease of Oxygenation Index (OI) after compassionate treatment with NO from TAS + PLUS device.The device showed effectiveness and safety both in experimental PH and in the clinical setting. Therefore, it represents an excellent alternative for PPHN management in conditions where commercial NO is unavailable.

Validation of an Immunoassay for Anti-thymidine Phosphorylase Antibodies in Patients with MNGIE Treated with Enzyme Replacement Therapy

Erythrocyte encapsulated thymidine phosphorylase is recombinant Escherichia coli thymidine phosphorylase encapsulated within human autologous erythrocytes and is under development as an enzyme replacement therapy for the ultra-rare inherited metabolic disorder mitochondrial neurogastrointestinal encephalomyopathy. This study describes the method validation of a two-step bridging electrochemiluminescence immunoassay for the detection of anti-thymidine phosphorylase antibodies in human serum according to current industry practice and regulatory guidelines. The analytical method was assessed for screening cut point, specificity, selectivity, precision, prozone effect, drug tolerance, and stability. Key findings were a correction factor of 129 relative light units for the cut-point determination; a specificity cut point of 93% inhibition; confirmed intra-assay and inter-assay precision; assay sensitivity of 356 ng/mL; no matrix or prozone effects up to 25,900 ng/mL; a drug tolerance of 156 ng/mL; and stability at room temperature for 24 hr and up to five freeze-thaws. Immunogenicity evaluations of serum from three patients who received erythrocyte encapsulated thymidine phosphorylase under a compassionate treatment program showed specific anti-thymidine phosphorylase antibodies in one patient. To conclude, a sensitive, specific, and selective immunoassay has been validated for the measurement of anti-thymidine phosphorylase antibodies; this will be utilized in a phase II pivotal clinical trial of erythrocyte encapsulated thymidine phosphorylase.

Widows’ Men: The Admiralty Board, Precedent, and Pensions for the Widows of the Lost Franklin Expedition

ABSTRACTWhen the British Admiralty announced in January, 1854 that it intended to strike the names of the officers of Sir John Franklin's missing polar expedition off the active Navy List, it had years of legal precedent to support its right to do so. The Board used such precedent to its advantage in ending a search its members had considered fruitless since 1849, the year the expedition's food would have run out. However, in their treatment of the widows made from that decision, Board members consistently pushed against established practice in order to do what they felt was right: to give the widows as generous a pension as the Treasury would approve, and to do so in defiance of the strict rules of eligibility. In 1844, only months before Franklin and 128 men set forth to discover the Northwest Passage, new eligibility guidelines were set that both limited women's access to pensions, and hampered the Board's ability to grant them. Archival evidence that forms the core of this article shows, however, that compassionate treatment of the expedition's widows was central to all discussions of how the Admiralty might move forward on the Franklin disaster, between promoting officers in absentia in order to augment pensions, to waiving the need for proving the date of death in order for families to collect the explorers’ back pay. As this article argues, the 1854 Admiralty Board had powerfully split loyalties: on the one hand, as the press acknowledged, the Board had a duty to perform on behalf of the public, to avoid wasting the nation's money on frivolous or useless searches for men assumed to be long dead; on the other hand, it felt equally strongly the obligation to support those widows who were the product of such imperial adventuring, even in defiance of its own rules. Through an analysis of legal precedent, Naval Instructions, and private Admiralty Board documents, in the case of the Franklin expedition's widows one can perceive a few naval administrators who tried to keep some of the nation's most vulnerable citizens in view even as they managed the bottom line.

Abstract 586: Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone

Abstract Human leukemia cancer cell line studies have demonstrated the presence of a 34 kDa intracytoplasmic splice variant of the parent 90 kDa nuclear protein associated with the centrosome that has significant immunosuppressive activity, especially, but not limited to natural killer (NK) cells. One mechanism of suppressing NK cell cytotoxicity is by stabilizing perforin granules. The 34 kDa intracytoplasmic isoform has been shown to be present only in rapidly growing cells, e.g., embryonic, mesenchymal, trophoblast, and cancer cells. During the luteal phase in ovulating women, and throughout pregnancy, there is a rise in the serum level of this immunomodulatory protein. Thus, it is called the progesterone induced blocking factor (PIBF). Interestingly, the abortafacient, mifepristone, has been shown to suppress the 34 kDa intracytoplasmic concentration of PIBF in cancer cell lines, but it does not lower serum PIBF. Based on the demonstration of significant increase in quality and length of life in controlled animal studies, and anecdotal experience in compassionate use treatment of human patients with a variety of advanced cancer types, the FDA has granted an investigator initiated salvage study of 40 patients with advanced non-small cell lung cancer (NSCLC) who have failed a minimum of two rounds of chemo or immunotherapy to be treated with single agent oral mifepristone (www.clinicaltrials.gov). The first 2 patients are doing extremely well (2 years and 1 year so far) with a high quality life without significant disease progression. Sera PIBF levels were obtained on these patients every 2 months using an experimental ELISA assay. For patient 1, a man with stage IV NSCLC with brain metastasis, his PIBF levels (ng/ml) were all in the range of normal males and women in the follicular phase (27, 38, 53, 59, 52, 46, 39, 45, 44, and 49). For patient 2, who is a female positive for the PD-L1 marker, and who progressed despite 3 rounds of chemotherapy and 1 round of nivolumab, her levels were 10, 30, 12, 21, 23, 50, 64, and 30. Thus, these results suggest that measuring serum PIBF levels in patients with very advanced NSCLC has little value in determining which patients will respond to the progesterone receptor modulator mifepristone, or be able to monitor their response to progesterone receptor modulator therapy. Citation Format: Jerome H. Check, Diane Check, Maya Srivastava, Ann DiAntonio. Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 586.

EAPH-10. SUCCESSFUL TREATMENT OF A SECONDARY PEDIATRIC HIGH GRADE GLIOMA WITH A NOVEL BEND4-NTRK2 FUSION WITH ENTRECTINIB, A TRK INHIBITOR

A 2 month old child with a large hemispheric tumor; after subtotal resection, pathology showed pilomyxoid astrocytoma with BRAFV600E mutation by immunohistochemistry and pyrosequencing. He had multiple episodes of radiographic and clinical progression. Over the course of 5 years, therapy included carboplatin, TPCV, velban, and immunotherapy. Vemurafenib and dabrafenib were administered with no response. MRI showed rapid tumor progression in the brain with spinal dissemination and significant clinical deterioration. Patient underwent tumor debulking and pathology confirmed a high grade astrocytoma, without BRAF V600E mutation, but with a novel BEND4-NTRK2 fusion by molecular genetic testing. He underwent whole brain radiation of 33 Gy in 16 fractions and boost to primary tumor bed to a total dose of 43 Gy. No radiation was given to the spine. One month later, patient started compassionate treatment with entrectinib, a novel, CNS-active, TRK inhibitor, at 400 mg/m2/day. MRI obtained after 28 days on treatment demonstrated significant radiographic regression, with rapid improvement in clinical symptoms. His dose was then increased to 550 mg/m2/day. After 2 additional cycles, the tumor continues to decrease in size in the brain and a spine MRI demonstrated complete response despite no radiation to the spine. Toxicities included Grade 1 ALT, cholesterol and peripheral edema. In summary, we report the case of a refractory BRAF V600E mutated low grade glioma transformed into a high grade with a novel BEND4-NTRK2 fusion, and profound radiographic and clinical response to entrectinib.

The moment of truth: Proust, Barthes, and the contingency of old age

ABSTRACTIn his Preface to the Life of Rancé, Roland Barthes raised a set of questions about how to write about old age. A decade and a half later, proposing a new start for himself as a writer, he takes as his model Marcel Proust, a writer who rehabilitates the idea of pity in relation to ageing, and makes an encounter with old age a final turning point in his novel. The current reading of Proust, using Barthes’s thoughts on both old age and Proust as a frame, argues for a much more selectively compassionate treatment of old age than Barthes claims for Proust, and questions the place of old age in Proust’s aesthetic and intellectual scheme. Adam Phillips has argued that Proust is, in opening himself to accidental encounters with the past, also more comfortable than other writers with the contingency of the future, and death’s imperviousness to prediction and control. Ageing and the approach of death are starkly depicted in the final volume of Proust’s work, it is true, but their effects are mitigated by the constants of hierarchy and privilege in Proust’s fictional world, and the question of what their depiction is for remains moot.

Krivične sankcije i programi ranog otpusta zatvorenika

The punishment of criminals is a long-debated topic in penology, criminology, and sociology of law. But it has an underdeveloped history in philosophy generally, and in philosophy of law in particular. Philosophical discussions of early release programs is particularly lacking in philosophy of law and moral philosophy. But in the State of California, there are several citizens who believe that criminals ought to be treated with much more compassion than is currently the case (as they see it) and all that this seemingly implies, while there are those who argue for a compassionate but harsher treatment of criminals. This paper is an attempt to provide some philosophical clarity to some of the legal, economic and moral questions pertaining to whether or not proposed early release programs in California concerning criminal punishment are justified.

Thoughts on the Immigration Debate and Health Care: A Personal Story.

Thoughts on the Immigration Debate and Health Care: A Personal Story.

Autism, theory of mind, and the reactive attitudes.

Whether to treat autism as exculpatory in any given circumstance appears to be influenced both by models of autism and by theories of moral responsibility. This article looks at one particular combination of theories: autism as theory of mind challenges and moral responsibility as requiring appropriate experience of the reactive attitudes. In pursuing this particular combination of ideas, we do not intend to endorse them. Our goal is, instead, to explore the implications of this combination of especially prominent ideas about autism and about moral responsibility. These implications can be quite serious and practical for autists and those who interact directly with autists, as well as for broader communities as they attend to the fair, compassionate, and respectful treatment of increasing numbers of autistic adults. We find that these theories point to a limited range of situations in which autists should not be blamed for transgressive actions for which neurotypical individuals should be blamed. We build on what others have written on these issues by bringing in a recent cognitive model of the role theory of mind plays in empathy, by discussing the social implications of the theoretical findings, and by raising questions about the compatibility of reactive attitude theories of moral responsibility with the neurodiversity approach to autism.

A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C)

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options. Genervon has discovered and developed GM604 (GM6) as a potential ALS therapy. GM6 has been modeled upon an insulin receptor tyrosine kinase binding motoneuronotrophic factor within the developing central nervous system. Methods This was a 2-center phase 2A, randomized, double-blind, placebo-controlled pilot trial with 12 definite ALS patients diagnosed within 2 years of disease onset. Patients received 6 doses of GM604 or placebo, administered as slow IV bolus injections (3x/week, 2 consecutive weeks). Objectives were to assess the safety and efficacy of GM604 based on ALSFRS-R, FVC and selected biomarkers (TDP-43, Tau and SOD1, pNFH). This report also includes results of compassionate treatment protocol GALS-C for an advanced ALS patient. Results Definite ALS patients were randomized to one of two treatment groups (GM604, n = 8; placebo, n = 4). 2 of 8 GM604-treated patients exhibited mild rash, but otherwise adverse event frequency was similar in treated and placebo groups. GM604 slowed functional decline (ALSFRS-R) when compared to a historical control (P = 0.005). At one study site, a statistically significant difference between treatment and control groups was found when comparing changes in respiratory function (FVC) between baseline and week 12 (P = 0.027). GM604 decreased plasma levels of key ALS biomarkers relative to the placebo group (TDP-43, P = 0.008; Tau, P = 0.037; SOD1, P = 0.009). The advanced ALS patient in compassionate treatment demonstrated improved speech, oral fluid consumption, mouth suction with GM604 treatment and biomarker improvements. Conclusions We observed favorable shifts in ALS biomarkers and improved functional measures during the Phase 2A study as well as in an advanced ALS patient. Although a larger trial is needed to confirm these findings, the present data are encouraging and support GM604 as an ALS drug candidate.

113 Compassionate nitric oxide adjuvant treatment of persistent Mycobacterium infection in cystic fibrosis patients

113 Compassionate nitric oxide adjuvant treatment of persistent Mycobacterium infection in cystic fibrosis patients