Lung Disease

October 31, 2016

Insmed reported results of a phase II study of Arikayce (liposomal amikacin for inhalation or LAI) for treatment-refractory nontuberculous mycobacterial (NTM) lung disease. The study was a randomized, double-blind, placebo-controlled study. Subjects were randomized 1:1 either to Arikayce once-daily plus a multi-drug regimen or to placebo once-daily plus a multi-drug regimen. Subjects had the option of continuing in an 84-day open-label phase. The study also included 28-day and 12-month off-Arikayce follow-up assessments. Eighty-nine subjects were randomized and dosed in the study. Of the 80 subjects who completed the 84-day double-blind phase, 78 subjects entered the open-label phase during which all patients received Arikayce plus a multi-drug regimen for 84 days. Seventy-six (76) percent (59/78) of subjects who entered the open-label phase of the study completed the open-label study. The primary efficacy endpoint of the study was the change from baseline (day 1) to the end of the double-blind phase of the trial (day 84) in a semi-quantitative measurement of mycobacterial density on a seven-point scale. The primary endpoint did not reach statistical significance; however, a positive numerical trend in favor of Arikayce was observed (p=0.072). The p-value for the key secondary endpoint of culture conversion to negative at day 84 was 0.003, in favor of Arikayce. A shorter time to first negative sputum culture was also observed with Arikayce relative to placebo during the double-blind phase (p=0.013).

February 8, 2016

OncoGenex Pharmaceuticals reported results of a phase II trial evaluating the combination of apatorsen with carboplatin and pemetrexed in patients with untreated metastatic non-small cell lung cancer (NSCLC). Data did not reach the statistical significance required to demonstrate a progression-free survival (PFS) benefit. The placebo-controlled, double-blind, randomized trial enrolled 155 subjects. A potential PFS benefit was observed in patients with high baseline serum Hsp27 status when treated with apatorsen. The study is ongoing and overall survival results are expected in the second half of 2016. Treatment and maintenance therapy with apatorsen was well-tolerated. Adverse events were comparable between the arms and as expected for the study chemotherapy treatment.  

November 16, 2015

Merck has reported results of a randomized, pivotal phase II/III study comparing two doses of Keytruda (the FDA-approved 2mg/kg dose and a higher, investigational 10mg/kg dose, each given every three weeks) to docetaxel, a commonly used chemotherapy, for advanced non-small-cell lung cancer (NSCLC). KEYNOTE-010 is a global, open-label study in 1,034 patients. A topline analysis revealed that treatment with Keytruda was associated with longer overall survival (OS) compared with docetaxel treatment. That result was true for both the approved and the investigational dose of Keytruda, which showed similar efficacy. It was also true in both the first set of patients analyzed—those with a tumor proportion scores (TPS) of 50% or greater and for all enrolled patients, all of whom had a TPS of 1% or greater. Treatment with Keytruda, at both doses, also provided superior progression-free survival (PFS) v. that achieved following treatment with docetaxel in patients whose tumors had TPS values equal to or greater than 50%. For PFS, Keytruda treatment was numerically but not statistically superior to docetaxel in the all PD-L1 positive group, again at both doses. The safety profile of Keytruda in that trial was consistent with that observed in previously reported studies in patients with advanced NSCLC.

November 2, 2015

Immunomedics has reported results of a phase III trial of sacituzumab govitecan for metastatic triple-negative breast (TNBC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers. At the time of analysis, 56 enrolled patients had received sacituzumab govitecan at the optimal dose of 10mg/kg given on days one and eight of a three-week cycle. Treatment response was available for 52 patients. The objective response rate was 29% (15/52), with two confirmed complete responses. The interim median progression-free survival (PFS), a measure of time patients are living without their cancer progressing, was seven months. Forty-six percent of these TNBC patients had experienced a PFS event. Overall survival (OS) data were too early to report because 86% of patients are still alive. For metastatic lung cancers, 33 patients with NSCLC were enrolled to receive sacituzumab govitecan at the or 10mg/kg dose level. Among 29 patients assessable, an objective response rate of 28% (8/29) was observed, including patients with both squamous cell and adenocarcinoma NSCLC types. For the 25 patients at the 10mg/kg dose, the interim median PFS was 3.8 months, with 48% of patients in this dose group having experienced a PFS event. In SCLC, of the 27 patients enrolled at doses of 8mg/kg and 10mg/kg, 25 were assessable for response. Six patients achieved a partial response (objective response rate=24%). Interim median PFS for the 12 patients at the 10mg/kg dose level was 3.6 months and 83% of patients had experienced a PFS event. Since 96% of NSCLC patients and 100% of SCLC patients were still alive at the time of analysis, OS data at the optimal dose of 10mg/kg are too early to report. Sacituzumab govitecan has received Fast Track designation from the FDA for the treatment of patients with TNBC, SCLC and NSCLC, and also has been designated an orphan drug for SCLC or pancreatic cancer in the U.S., and for the treatment of patients with pancreatic cancer in the E.U.

October 26, 2015

BeyondSpring Pharmaceuticals has released results of a phase III study of Plinabulin combined with docetaxel for non-small cell lung cancer (NSCLC) in patients who have lung lesions greater than 3cm. Patients were randomized one-to-one in a Plinabulin plus docetaxel treatment arm compared to docetaxel alone. Patients in the treatment arm received 30mg/m2 dose of Plinabulin, which was selected as the dose for an ongoing phase III study. Analysis of median overall survival (OS) according to tumor size of any lesion demonstrated evident OS benefit in favor of Plinabulin and docetaxel treatment arm, as shown by hazard ratio (HR). In patients with lesions greater than 3 cm, HR gradually decreased to <0.6. The HR range was 0.97-0.50. That trend was consistently observed independent of number of prior treatments. The importance of location of lesions also was analyzed. It was apparent that patients with advanced lesions in lung parenchyma received more benefit from Plinabulin plus docetaxel treatment (HR=0.76) regardless of lesion size. The HR range (0.84-0.44) based on lung lesion size also was consistent with findings based on size of all lesion including extra-pulmonary lesions. Treatment with Plinabulin plus docetaxel was well-tolerated, with most common adverse events consistent with chemotherapy side effects and including nausea, fatigue, diarrhea, constipation, anorexia, fever, vomiting and transient blood pressure elevation, which were mostly grade 1-2.

June 29, 2015

Boehringer Ingelheim issued results of a phase III study of afatinib v. erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung, progressing after treatment with first-line chemotherapy. Treatment with afatinib significantly reduced the risk of death by 19%, extending the survival of patients to a median of 7.9 months compared to 6.8 months on erlotinib. Significantly more patients treated with afatinib were still alive at one year compared to those treated with erlotinib (36.4 v. 28.2%). The updated analysis of PFS confirmed a significant reduction in the risk of cancer progression by 19% in patients treated with afatinib compared with erlotinib. The delay in cancer progression seen with afatinib treatment was accompanied by improved control of cancer-related symptoms: a higher proportion of patients treated with afatinib reported improvement in cough (43.4 v. 35.2%), shortness of breath (51.3 v. 44.1%) and overall well-being/quality-of-life (35.7 v. 28.3%) compared with erlotinib. The rate of severe adverse events was similar between afatinib and erlotinib treatment arms (57.1 v. 57.5%). Afatinib is approved in more than 50 countries for the first-line treatment of distinct types of EGFR mutation-positive NSCLC. Afatinib is not approved for use in patients with SCC of the lung. The complete results from this study will be the basis for global regulatory submissions later this year.

March 2, 2015

Immunomedics reported results of a study of sacituzumab govitecan for treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). A total of 44 heavily-pretreated patients with relapsed or refractory lung cancer have been enrolled into this multicenter study. At the time of analysis, 16 patients with SCLC and 18 with NSCLC were evaluated by computed tomography for response and time-to-progression (TTP). Despite the late-stage setting, TTP for most patients was longer with sacituzumab govitecan than the duration of their previous lung cancer therapy. 33% of patients with SCLC and 31% with NSCLC had their tumor reduced in size by 30% or more. Sacituzumab govitecan controlled the progression of the cancer in 75% and 56% of NSCLC and SCLC patients, respectively. These patients had either failed to respond to their last lung cancer therapies or their cancer had returned or progressed. Sacituzumab govitecan continues to produce an acceptable safety profile in heavily-pretreated patients, with neutropenia (24% grades three and four combined) as the major toxicity. Diarrhea, the typical side effect of irinotecan treatment, was minimal at 3% grade three. More importantly, repeated efficacious doses of the ADC can be given to patients over months without evoking any interfering immune response.

February 9, 2015

Boehringer Ingelheim released results of two phase III trials of afatinib compared to standard chemotherapy for epidermal growth factor receptor (EGFR) mutation-positive patients with metastatic non-small cell lung cancer (NSCLC). In the two individual phase III studies, treatment-naïve patients with stage IIIB/IV lung adenocarcinoma and confirmed EGFR mutations in the tumor were enrolled in LUX-Lung 3 (n=345; recruited globally) and LUX-Lung 6 (n=364; recruited in China, Korea and Thailand). Patients were randomized (2:1) to receive oral afatinib (40mg/day) or up to six cycles of intravenous pemetrexed/cisplatin (LUXLung 3) or gemcitabine/cisplatin (LUX-Lung 6) at standard doses. Stratification factors included EGFR mutation type (Del19 v. L858R v. other “uncommon” mutations) and race (Asian v. non-Asian; LUX-Lung 3 only). Results from both trials showed similar OS in the afatinib and chemotherapy arms in the overall NSCLC EGFR mutation-positive population (LUX-Lung 3: median OS 28.2 to 28.2 months, HR 0.88; p=0.39); (LUX-Lung 6: median OS 23.1 to 23.5 months, HR 0.93; p=0.61). There was a survival benefit of more than a year (LUX-Lung 3: median OS 33.3 to 21.1 months; HR 0.54; p=0.0015); (LUX-Lung 6: median OS 31.4 to 18.4 months; HR 0.64; p=0.0229).

November 10, 2014

Bristol-Myers Squibb reported results from a phase II, single-arm, open-label study of Opdivo (nivolumab) in patients with advanced squamous cell non-small cell lung cancer (NSCLC) who have progressed after at least two prior systemic treatments with 65% receiving three or more prior therapies (n=117). The trial, Checkmate -063, was designed to assess advanced squamous cell NSCLC patients who progressed after both platinum-based therapy and at least one additional systemic therapy, with an ECOG Performance Status of zero or one. Subjects were treated with Opdivo as a single agent 3mg/kg by intravenous infusion every two weeks until disease progression or treatment discontinuation (n=117). With approximately 11 months of minimum follow up, the objective response rate (ORR, the study’s primary endpoint) was 15% (95% CI = 8.7, 22.2) as assessed by an independent review committee (IRC) using RECIST 1.1 criteria, and the median duration of response was not reached. The estimated one-year survival rate was 41% (95% CI = 31.6, 49.7) and median overall survival (mOS) was 8.2 months (95% CI = 6.05, 10.91). Grade 3-4 drug-related adverse events (AEs) were reported in 17.1% of patients. The most common Grade 3-4 AEs (greater than or equal to 2%) were fatigue (4.3%), pneumonitis (3.4%) and diarrhea (2.6%). Discontinuations due to drug-related AEs of any grade occurred in 12% of patients, and there were two drug-related deaths in patients with multiple co-morbidities and in the setting of progressive disease.

October 20, 2014

Puma Biotechnology issued results of a phase II trial of PB272 (neratinib) for the treatment of non-small cell lung cancer (NSCLC) with HER2 mutations. In the trial, patients with confirmed stage IIIB or stage IV NSCLC with documented somatic HER2 mutations were randomized to receive either oral neratinib monotherapy, 240mg per day, or the combination of oral neratinib, 240mg daily, with intravenous temsirolimus administered at a dose of 8mg per week. A total of 27 patients completed the first stage of the trial; 13 of these patients received neratinib monotherapy and 14 of these patients received the combination of neratinib plus temsirolimus. Results showed that of the 13 patients who received neratinib monotherapy, no patient experienced a partial response, seven (54%) patients achieved stable disease and four (31%) patients achieved clinical benefit (defined as a partial response or stable disease for 12 or more weeks). For the 14 patients who received the combination of neratinib plus temsirolimus, three (21%) patients experienced a partial response, 11 (79%) patients experienced stable disease and nine (64%) patients achieved clinical benefit. The median progression free survival of the neratinib monotherapy arm was 2.9 months and the median progression free survival of the arm that received neratinib plus temsirolimus was four months. Patients continue to be enrolled in the arm of the trial that is receiving the combination of neratinib plus temsirolimus.

June 23, 2014

Novartis reported phase I trial results of Zykadia (LDK378) in patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). The 246 patients with ALK+ NSCLC in this single-arm study received ceritinib 750mg ALK+ daily. Findings from the study showed patients treated with ceritinib achieved an ORR of 58.5% [95% CI, 52.1-64.8%] and a median PFS of 8.2 months [95% CI, 6.7-10.1 months]. The median duration of response was 9.7 months [95% CI, 7.0-11.4 months], with a median time to first response of six weeks after starting treatment. Among 163 patients receiving 750 mg of ceritinib daily and who were previously treated with the commonly prescribed ALK inhibitor crizotinib, ORR was 54.6% [95% CI, 46.6-62.4%] and PFS was 6.9 months [95% CI, 5.4-8.4 months]. In 83 patients who had not received prior treatment with an ALK inhibitor, ORR was 66.3% [95% CI, 55.1-76.3%] and PFS had not been reached. In the 124 patients who started the study with brain metastases, ceritinib achieved an ORR of 54.0% [95% CI, 44.9-63.0%] and a median PFS of 6.9 months [95% CI, 5.4-8.4 months]. Tumor shrinkage was seen in 50.0% of patients [49 of 98 patients; 95% CI, 39.7-60.3%] with brain metastases who had received previous ALK inhibitor therapy, while 69.2% of patients [18 of 26 patients; 95% CI, 48.2-85.7%] with brain metastases who were not previously treated achieved tumor shrinkage following treatment with ceritinib.

May 6, 2013

Almirall and Forest Laboratories issued results from a phase III trial of aclidinium bromide and formoterol fumarate for the treatment of moderate to severe chronic obstructive pulmonary disease. This 24-week, randomized, double-blind study enrolled 1,729 patients with COPD. Subjects received 400/6mcg and 400/12mcg fixed doses of aclidinium bromide/formoterol fumarate, or aclidinium bromide 400mcg alone, formoterol fumarate 12mcg alone or placebo, administered twice daily through the Genuair/Pressair inhalers. Results showed that both combinations of aclidinium/formoterol (400/6mcg and 400/12mcg given twice a day) demonstrated statistically significant improvements in the co-primary endpoints of change from baseline in morning pre-dose trough FEV1 versus formoterol 12mcg alone and in FEV1 at 1 hour post-dose versus aclidinium 400mcg alone at week 24. For the second co-primary endpoint of change from baseline in FEV1 at 1 hour post-dose versus aclidinium 400mcg, aclidinium/formoterol 400/6mcg and 400/12mcg demonstrated statistically significant improvements versus aclidinium 400mcg (69mL and 125mL, respectively) and placebo (244mL and 299mL, respectively). Both fixed-dose combination treatment arms were well tolerated in this study. The most frequent adverse events were nasopharyngitis and back pain. Based on these results, and expected results from a second phase III trial, Almirall and Forest Laboratories will file an NDA with the FDA and an MAA to the EMA.

September 10, 2012

Boehringer Ingelheim released results from a phase II adjunctive trial of tiotropium for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, double-blind, four-period, crossover study enrolled 232 patients with post-bronchodilator FEV1 of ≥30% and <80% of predicted normal. Subjects received tiotropium 1.25μg, 2.5μg or 5μg in combination with olodaterol 5μg or 10μg, or olodaterol and placebo, for four weeks. Results showed the free combination of tiotropium and olodaterol provided an average lung function improvement of up to 342mL over the first six hours after four weeks of treatment (FEV1 AUC0-6) compared to pre-dose lung function mean baseline values and improvements in trough FEV1 of up to 166mL, compared to pre-treatment FEV1 mean baseline values. Tiotropium was well tolerated. The most frequent adverse events were nasopharyngitis and COPD. This study completes a comprehensive phase II program to thoroughly investigate different doses of each active component to identify the appropriate doses for the fixed-dose combination.

Elevation Pharmaceuticals issued results from a phase IIb trial of EP-101 for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, placebo-controlled, double-blind, seven-arm, four-period cross-over, block design, dose-ranging study, GOLDEN-1, enrolled 140 patients with moderate to severe COPD. Subjects received EP-101 25μg, 50μg, 100μg or 200μg daily or placebo for seven days. Data demonstrated that all doses of EP-101 showed a rapid onset, dose-related, statistically significant improvement in lung function compared to placebo. Improvements in lung function with EP-101 doses were comparable to those of once-daily tiotropium dry powder inhaler and three-times daily nebulized ipratropium administered via jet nebulizer. The drug was well tolerated. The most frequent adverse events were cough and headache. Elevation Pharmaceuticals will be initiating a second phase IIb study in Q4 2012 to select the dose for phase III studies.

September 3, 2012

MediciNova reported preliminary results from a phase Ib trial of MN-221 for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, placebo-controlled study enrolled 25 patients with stable, moderate-to-severe COPD. Subjects received six intravenous infusions of 1200µg MN-221 or placebo over four days. Results indicate moderately improved pulmonary function (FEV1) in MN-221 recipients, but not the placebo recipients. Moreover, the improvement of FEV1 on subsequent MN-221 dosing days was as good as or better than on day one. In addition, there was no significant ccumulation of plasma MN-221 over the multiple dosing intervals. The drug was well tolerated. Two MN-221 recipients with pre-existing heart disorders were terminated from the study due to transient arrhythmias identified by electrocardiograph monitoring that did not have clinical symptoms or consequences and resolved spontaneously. MediciNova will meet with the FDA in October for an end-of-phase II meeting.

June 18, 2012

Otsuka Pharmaceutical reported results from a phase IIb trial of delamanid for the treatment of multidrug-resistant tuberculosis. This multinational, double-blind, randomized, placebo-controlled study enrolled 481 patients. Subjects received delamanid 100mg or 200mg twice daily in combination with background regimen, or placebo plus background regimen for eight weeks. Results showed 45.4% of subjects in the delamanid 100mg arm (p≡0.008) and 41.9% of subjects in the delamanid 200mg arm (p≡0.039) achieved sputum culture conversion (SCC) in the Mycobacterial Growth Indicator Tube (MGIT) system after two months of treatment, compared with 29.6% of subjects in the placebo arm. Adverse events were comparable among all three arms, the most common being QT prolongation on electrocardiogram. Based on these data, Otsuka initiated a phase III trial of delamanid, including subjects receiving anti-retroviral drugs for co-existing HIV infection.

October 23, 2006

Discovery Laboratories announced positive top line results from phase II trial of Surfaxin for the prevention and treatment of Bronchopulmonary Dysplasia (BPD), a disease affecting premature infants. This randomized, double-blind, placebo-controlled trial enrolled 136 premature infants. Subjects received Surfaxin at a standard dose (175 mg/kg), Surfaxin at a low dose (90 mg/kg), or sham air as a control, up to five times a day. Therapy was safe and well tolerated in the treatment and control groups with no differences in adverse events noted between the groups. Efficacy data revealed a positive pharmacological response to Surfaxin therapy with a noted reduction in supplemental oxygen and ventilatory support compared to the control group. Additionally, when compared with controls, the subjects receiving the standard dose Surfaxin therapy had a lower incidence of death or BPD (57.8% vs. 65.9%) and a higher survival rate through 36 weeks post-menstrual age (88.9% vs. 84.1%). Based on this data Discovery plans to move the development of Surfaxin forward.

July 4, 2005

PTC Therapeutics announced positive results of a pair of phase I studies of PTC124, their investigational drug targeting nonsense mutations in cystic fibrosis (CF) and Duchenne muscular dystrophy (DMD), at the 28th Annual European Cystic Fibrosis Conference. Trial data met primary safety and pharmacokinetic endpoints: no serious adverse events were reported, overall tolerability was positive, target plasma concentrations were achieved, and an optimal dosing regimen for future trials has been established. Pharmacogenetic analysis indicated that the drug did not induce unintended read-through of normal, healthy stop codons. These single- and multiple-dose studies enrolled healthy volunteers. The company announced plans to initiate phase II studies of the drug for the treatment of CF, based on these results.

October 7, 2002

Results of a phase II trial suggested that SCV-07 significantly increased the rate by which tuberculosis subjects became noncontagious. In the study, 80% (35/44) of tuberculosis subjects who underwent standard anti-TB chemotherapy were no longer contagious (measured by negative sputum cultures) three months after also receiving a five-day regimen of parenteral SCV-07 therapy. 37% (10/27) of subjects whose therapy did not include SCV-07 were no longer contagious. All the subjects receiving SCV-07 reported an improvement in symptoms including fever and cough. There was also a significant decrease in the number of subjects with lung damage. SCV-07 is a product of Sciclone Pharmaceuticals.

July 15, 2002

Positive results were reported from a phase I/II trial of NicOx's NCX 950, an inhaled nitric oxide-donating drug for respiratory diseases. The randomized, double-blind, placebo-controlled trial was conducted in Switzerland and included 24 healthy subjects. The study was designed to compare treatment with an inhaled formulation of NCX 950 to treatment with salbutamol sulphate and placebo. Results indicated that NCX 950 was safe and well tolerated. Furthermore, data showed equipotency for NCX 950 in terms of bronchodilation and a faster onset of action compared to salbutamol.

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