Bristol-Myers Updates Efficacy Data from Phase 2 Multiple Myeloma Trial

• In a descriptive analysis, addition of Empliciti to pomalidomide and dexamethasone reduced risk of death by 46% among patients with RRMM
• Empliciti-based combination showed improvements across efficacy endpoints, including continued progression-free survival benefit at 18 months

Bristol-Myers Squibb Company (NYSE: BMY) today announced the presentation of updated data from ELOQUENT-3, the international randomized Phase 2 study evaluating Empliciti (elotuzumab) plus pomalidomide and dexamethasone (EPd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed or refractory multiple myeloma (RRMM). In a non-prespecified analysis conducted to provide a descriptive assessment of overall survival (OS) after extended follow-up of at least 18.3 months, patients treated with EPd continued to experience sustained and clinically relevant OS and progression-free survival (PFS) benefits compared with patients treated with Pd.

Treatment with EPd was associated with a 46% reduction in risk of death [Hazard Ratio (HR) 0.54; 95% Confidence Interval (CI): 0.30 to 0.96] versus treatment with Pd alone. At 18 months, rates of OS, a secondary endpoint, were 68% for patients treated with EPd compared to 49% for patients treated with Pd. Median OS was not reached with EPd [95% CI: 24.9 months, Not Estimable (NE)] at the time of analysis and was 17.4 months (95% CI: 13.8, NE) among patients receiving Pd. Eighteen-month PFS rates were 34% among patients randomized to EPd compared to 11% among patients randomized to Pd. Safety results for EPd were consistent with the primary analysis and with prior findings for Empliciti and pomalidomide regimens.

These data will be presented at the 24^th Congress of the European Hematology Association (EHA) in Amsterdam in a poster display (Abstract #PS1370) on Saturday, June 15 from 5:30-7 PM CEST.

https://www.biospace.com/article/releases/bristol-myers-squibb-presents-updated-efficacy-data-from-phase-2-trial-of-empliciti-elotuzumab-plus-pomalidomide-and-dexamethasone-in-patients-with-relapsed-or-refractory-multiple-myeloma-rrmm-/

Chi-Med Halts Phase III Study Early After Meeting Primary Endpoint

Hutchison China MediTech Limited, better known as Chi-Med, halted a late-stage study earlyafter an interim analysis showed surufatinib hit the primary endpoint of progression-free survival in advanced non-pancreatic neuroendocrine tumors.

In its announcement this morning, Chi-Med did not disclose the early results of the trial. It only noted that at the interim analysis, surufatinib “met the pre-defined primary endpoint” of PFS and halted the trial.

The Phase III study was being conducted in China. The results will allow Chi-Med to establish a pre-New Drug Application meeting with the China National Medical Products Administration ahead of filing for regulatory approval in that country. London-based Chi-Med added that it intends to submit the results of the Phase III Surufatinib in Advanced Neuroendocrine Tumors – Extra-Pancreatic (SANET-ep) trial to an unnamed upcoming medical conference.

Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Both receptors inhibit angiogenesis and colony stimulating factor-1 receptor, which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells, the company said.

The SANET-ep trial focused on patients with low- or intermediate-grade advanced extra-pancreatic neuroendocrine tumors who have not received effective treatment in the past from existing medications, such as Pfizer’s Sutent or Novartis’ Afinitor. In the study, patients were randomized at a 2:1 ratio to receive either 300 mg of surufatinib daily or placebo over the course of 28 days. In addition to PFS, secondary trial endpoints included objective response rate, disease control rate, time to response, duration of response, overall survival, safety and tolerability. Chi-Med will release full details of the results at the future conference.

In its announcement, Chi-Med said there were approximately 67,600 newly diagnosed neuroendocrine patients in 2018. The company estimated that there are about 490,000 patients living with the disease in the United States. Neuroendocrine tumors form in cells that interact with the nervous system or in glands that produce hormones. They are typically classified as pancreatic neuroendocrine tumors or other neuroendocrine tumors. Neuroendocrine tumors are associated with a relatively long duration of survival compared to other tumors.

In addition to neuroendocrine tumors, Chi-Med is also studying the safety and efficacy of surufatinib in other cancers. In March, the company initiated a Phase IIb/III study comparing surufatinib with capecitabine (sold as Xeloda in the U.S.) in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The first patient was dosed on March 22 in China.

https://www.biospace.com/article/chi-med-halts-phase-iii-study-early-after-interim-results-show-pfs-goal-was-met/

Enterovirus Believed at the Root of Rare, Polio-Like Disease

Acute flaccid myelitis is a rare, polio-like disease that has afflicted more than 500 children in the United States over the past five years. Researchers now believe they may have evidence a virus is at the root of the paralyzing condition.

First reported by STAT, researchers believe enterovirus D68 (EV-D68) could be one of the viruses at the core of the mysterious disease. The researchers used a method to pull evidence of viral infections from the spinal fluids of 42 patients with acute flaccid myelitis, STAT said. The fluids revealed the presence of EV-D68, as well as antibodies from enteroviruses, which are a group of viruses that include the polio virus. The researchers were quick to point out that their research is not definitive pinpointing EV-D68 as the culprit, but it’s regarded as a big step in understanding the source of the illness.

Michael Wilson, an assistant professor of neurology at the University of California, San Francisco (UCSF), who helped lead the research team, told STAT that the results of the research are a “roadmap for rapid development of enteroviral cerebrospinal fluid antibody assays” that will “enable efficient clinical diagnosis of enterovirus-associated AFM in the future.” While Wilson said the research suggests further development of those assays, he was quick to point out that the research conducted by his team has not been peer reviewed.

A preliminary report of data from Wilson’s research has been published in the preprint journal Biorxiv, STAT said. The U.S. Centers for Disease Control and Prevention, which took part in Wilson’s research, told STAT that the research found immune responses to enterovirus in spinal fluid. Such evidence, the CDC said, is an “important first step toward a diagnostic test for AFM and a path toward treatment.”

According to the CDC, there has been a significant rise of AFM patients since 2014. Of those, more than 90% had a mild respiratory illness or fever that was consistent with viral infection prior to the development of AFM. That’s one of the things that has made so difficult to diagnose. By the time the symptoms appear, the virus has typically cleared up, Wilson said. Last year the CDC report 232 cases of AFM and nine have so far been diagnosed in 2019.

The CDC said it has observed a pattern of the onset of the neurologic symptoms between August and October, which is the time of year that many viruses typically circulate, including enteroviruses.

While the research is promising, Wilson noted that more work has to be done before a definitive answer is agreed upon. Wilson told STAT that more work will have to be done to determine the thresholds for how much of the enterovirus antibody is needed to link it to AFM. Wilson and a team of researchers are using a bacteriophage method developed at Harvard Medical School to reach those answers. With that in hand, the work continues, he said.

https://www.biospace.com/article/research-indicates-an-enterovirus-is-at-the-root-of-acute-flaccid-myelitis/

Global Blood Therapeutics sickle cell trial hits endpoint ahead of NDA filing

Global Blood Therapeutics has shared updated data on the sickle cell disease trial it hopes will secure FDA approval of voxelotor. The proportion of patients who had a greater than 1 g/dL increase in hemoglobin is down on GBT’s prior update but still superior to placebo, resulting in the trial hitting its primary endpoint.

California-based GBT shared data on the first 154 patients to complete 24 weeks of follow-up in its phase 3 shortly after FDA green lit it to file for accelerated approval late last year. The data showed 65% of patients on the higher dose of voxelotor achieved the desired rise in hemoglobin, compared to 10% of people in the placebo cohort. Those figures came from a per-protocol analysis.

GBT now has 24-week data on all 274 patients enrolled in the trial of voxelotor, a stabilizer of sickle cell hemoglobin. On a per-protocol basis, 60% of patients in the higher-dose arm had a greater than 1 g/dL increase in hemoglobin, compared to 9% in the placebo cohort. The figures slipped to 51% and 7% in the intention-to-treat (ITT) analysis.

The lower, 900 mg dose of voxelotor performed worse than the other treatment arm but nonetheless statistically beat placebo, with respectively 33% and 38% of people in the ITT and per-protocol analyses clearing the hemoglobin bar.

Mean change in hemoglobin was down slightly on the prior data, too. The earlier update linked the higher-dose arm to a 1.4 g/dL mean increase. That figure slipped to 1.1 g/dL in the final analysis but even so comfortably outperformed placebo, which was associated with a decline of 0.1 g/dL.

GBT’s laser focus on hemoglobin is a relatively recent development. Going into the trial, GBT planned to break the study into two parts and rely on patient-reported outcomes (PROs) or vaso-occlusive crises (VOCs) as a key secondary endpoint and cornerstone of its regulatory strategy. That changed last year when GBT dropped the second part of the study and talked up the potential to win accelerated approval on the strength of hemoglobin data from the first stage of the trial.

The willingness of the FDA to accept the revised regulatory strategy was key for GBT. In the full analysis, voxelotor failed to drive statistically significant reductions in VOCs over placebo. And GBT has previously said the PROs generated uninterpretable results.

Those shortcomings leave scope to question the benefits of voxelotor. A New England Journal of Medicine editorial to accompany the release of the data identified both evidence that voxelotor delivers real benefits and concerns about its ability so far to move the needle against a key endpoint.

“The clinical significance of this response was the associated reduction in hemolysis, a consequence of sickle cell disease that is associated with chronic organ injury. A trend toward a cumulative reduction in the incidence of vaso-occlusive pain episodes with voxelotor as compared with placebo may be emerging in an extended follow-up analysis out to 72 weeks. Follow-up studies are needed to examine this very important, clinically relevant end point,” the author of the editorial wrote.

https://www.fiercebiotech.com/biotech/gbt-sickle-cell-trial-hits-endpoint-ahead-nda-filing

Bayer AG to cut environmental impact 30%, invest $5.6B for glyphosate alternate

Bayer AG, the parent of Monsanto, says it will cut its its environmental impact by 30% and invest $5.6 billion into find alternatives to its widely used glyphosate-based weed-killer RoundUp.

“While glyphosate will continue to play an important role in agriculture and in Bayer’s portfolio, the company is committed to offering more choices for growers and will invest approximately 5 billion euros in additional methods for combat weeds over the next decade,” Bayer said in a statement released Friday.

“This R&D investment will go towards improving the understanding of resistance mechanisms, discovering and developing new modes of actions, further developing tailored integrated weed management solutions and developing more precise recommendations through digital farming tools,” the German company said.

RoundUp is the world’s most popular herbicide.

Bayer AG, the parent of Monsanto, says it will invest $5.6 billion into find alternatives to its widely used glyphosate-based weed-killer RoundUp. (Photo: Haven Daley, AP)

Bayer, which purchased St. Louis-based Monsanto last year, faces mounting legal challenges after two California juries ruled in favor of men with lymphoma and blamed the herbicide for their disease. Bayer said it would appeal the court decisions.

Thousands of similar lawsuits are pending.

The company also said Friday it will use innovation to cut its agricultural footprint 30% by 2030.

“Bayer aims to achieve this by developing new technologies, scaling down crop protection volumes, and enabling more precise application,” the company said. “This will help to restore and retain biodiversity, combat climate change, and make the most efficient use of natural resources.”

Bayer, the maker of the glyphosate-based weed-killer RoundUp, says it will invest 5 billion euros — or $5.6 billion — into finding alternatives for its popular herbicide. (Photo: Nati Harnik, AP)

Bayer said it will work with weed scientists around the world to help “develop customized solutions for farmers at the local level.”

“The company will apply consistent safety standards to its products — even when it means exceeding local regulations,” the company said.

“Since 2012, Bayer has stopped selling all products that were considered acute toxicity class 1 by the World Health Organization, regardless of whether they were allowed in a particular market.”

The company also said it is “raising the bar in transparency.”

Bayer said it began releasing all of its safety-related crop science studies online last year for anyone to see. Since then, the company said it has released hundreds of studies for nearly 30 compounds, including all 107 company-owned glyphosate studies.

https://www.desmoinesregister.com/story/money/agriculture/2019/06/14/monsanto-parent-bayer-ag-investing-billions-find-alternatives-glyphosate-based-roundup-weed-killer/1446940001/

Krystal Submits Investigational New Drug Application for Topical Gene Therapy

KB105 is a new gene therapy candidate engineered with a Transglutaminase-1 (TGM1) gene construct to treat TGM1 deficient autosomal recessive congenital ichthyosis

KB105 is the second pipeline product based on the STAR-D platform and is part of a growing pipeline of gene therapy candidates for skin diseases

Krystal Biotech Inc., (“Krystal”) (NASDAQ: KRYS), a gene therapy company developing medicines to treat dermatological diseases, today announces that it has submitted an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to initiate a Phase 1/2, first in-human trial of KB105, an HSV-1 based gene therapy engineered to deliver a human transglutaminase-1 (TGM1) gene to patients with TGM1-deficient autosomal recessive congenital ichthyosis (ARCI).

TGM1-deficient ARCI is a debilitating rare skin disease characterized by excessive, thick scaling of the skin and causing multiple chronic health conditions. Leveraging its Skin Targeted Delivery (STAR-D) platform technology, Krystal’s approach is to use a non-replicating, non-integrating engineered HSV-1 virus, to deliver the TGM1 gene to dividing and non-dividing skin cells, causing them to produce the TGM1 protein that is lacking in this patient population. KB105 is designed to be an off-the-shelf treatment for TGM1-deficient ARCI that can be applied topically, directly to a patient’s skin.

“Advancing KB105 into the clinic is an important step for Krystal Biotech in our mission to bring life-changing treatments to people suffering from debilitating skin diseases,” said Suma Krishnan, founder and chief operating officer of Krystal. “As we head into the second half of 2019, we look forward to initiating a Phase 1/2 trial with KB105 and advancing KB103, our lead development candidate for dystrophic epidermolysis bullosa into a Phase 3 registration trial.”

https://www.globenewswire.com/news-release/2019/06/14/1868939/0/en/Krystal-Submits-Investigational-New-Drug-IND-Application-for-KB105-Topical-Gene-Therapy-Candidate-for-Transglutaminase-1-Deficient-Autosomal-Recessive-Congenital-Ichthyosis.html

Theravance, Mylan expand commercial pact to China, adjacent areas

Theravance Biopharma Ireland Limited, a subsidiary of Theravance Biopharma, Inc. (NASDAQ: TBPH) (“Theravance Biopharma”) and Mylan N.V. (NASDAQ: MYL) (“Mylan”) today announced the expansion of the companies’ current development and commercialization agreement for nebulized revefenacin to include China and certain adjacent territories. Revefenacin, marketed as YUPELRI^® in the U.S., is a long-acting muscarinic antagonist (LAMA), which is the first and only once-daily, nebulized bronchodilator approved for the treatment of chronic obstructive pulmonary disease (COPD) in the U.S.

It is estimated that COPD affects nearly 100 million individuals in China¹ with approximately 43 percent of those patients suffering from moderate to very severe forms of the disease². COPD is one of the top three causes of mortality in China, accounting for approximately 910,000 deaths annually³. COPD presents a significant financial burden to the healthcare system in China, contributing up to $266 billion in costs annually².

In 2015, Theravance Biopharma and Mylan, and their affiliates, established a strategic collaboration to develop and commercialize nebulized revefenacin products for COPD and other respiratory diseases in all global markets with the exception of China and adjacent territories. Under terms of the new agreement, Theravance Biopharma has granted Mylan exclusive development and commercialization rights to nebulized revefenacin in China and adjacent territories, which include Hong Kong SAR, the Macau SAR and Taiwan. In exchange, Theravance Biopharma will receive an upfront payment of $18.5 million and will be eligible to receive additional potential development and sales milestones totaling $54 million together with tiered royalties on net sales of nebulized revefenacin, if approved.  Mylan will be responsible for all aspects of development and commercialization in the partnered regions, including pre- and post-launch activities and product registration and all associated costs.

https://www.prnewswire.com/news-releases/theravance-biopharma-and-mylan-expand-yupelri-revefenacin-development-and-commercialization-agreement-to-include-china-and-adjacent-territories-300867648.html