BI-409306

In writing literally hundreds of stories this year, two BioSpace writers, Alex Keown and Mark Terry, found certain stories particularly intriguing or impactful. Some of those were such big topics that they were covered over a series of stories. Looking back at 2018, here are their Top 10. In writing literally hundreds of stories this year, two BioSpace writers, Alex Keown and Mark Terry, found certain stories particularly intriguing or impactful. Some of those were such big topics that they were covered over a series of stories. Looking back at 2018, here are their Top 10. #1. CRISPR Babies. He Jiankui , a researcher from the Southern University of Science and Technology of China announced that a set of twins had been born in which he had used CRISPR gene editing to modify the embryos. He made this announcement at the Second International Summit on Human Genome Editing held at the University of Hong Kong. He Jiankui modified the CCR5 gene, which should make the babies less susceptible to HIV infection. Another announcement He Jiankui made before leaving the conference to return to China was that there was another successful pregnancy. This has resulted in the widespread condemnation, calls for global guidelines, and the launch of numerous investigations, including by the China government and the U.S. National Institutes of Health (NIH). A group of more than 100 Chinese scientists co-signed a letter condemning it, calling it “crazy.” Other ethicists have called it “monstrous,” “unconscionable” and “a grave abuse of human rights.” #2. Takeda-Shire Deal. Although it was probably not in serious peril, shareholders of Japan’s Takeda Pharmaceutical voted to approve the acquisition of Dublin’s Shire in December. The deal is valued at $58 billion, the biggest single deal of the year. The deal came together in May 2018, with Takeda’s final official bid coming in at around $62.2 billion. Takeda made five public bids for the company. The deal came in at $30.33 per share in cash and 0.839 shares of Takeda stock. Currency fluctuations and Takeda’s share price drop brought the value down to about $58 billion. Takeda is gaining both Shire’s portfolio, heavy on rare disease drugs, and a stronger U.S. market presence. It’s also picking up a significant amount of debt, which pushes the deal closer to a total of $80 billion. And it is largely this debt that caused some problems leading up to today’s approval. As part of the final deal, Takeda has secured $30.9 billion in bank loans. A fairly small but vocal opposition group of Takeda shareholders calling itself “Think About Takeda’s Bright Future” or TTBF, made several attempts to scuttle the deal. At the June annual meeting, the group, which at the time had about 130 shareholders in it, expressed their opposition and advanced a proposal that would require advance shareholder approval be required for large acquisitions. The proposal, however, only received about 10 percent of votes in favor, failing to pick up wider opposition support. #3. Biotech IPOs and Moderna. It was a record year for biotech initial public offerings (IPOs). Some were individual record-breakers— Moderna Therapeutics , Allogene Therapeutics and Rubius Therapeutics . The total for the year is around $8.2 billion raised, breaking 2014’s record of $6.5 billion. Moderna sold approximately 26.3 million shares priced at $23 a share. This exceeded the revised goal of $600 million by about $4.3 million. The previous record was set two months ago by Allogene Therapeutics, when it raised $324 million at a $2.2 billion market cap. In July, Rubius Therapeutics’ IPO brought in $241 million. #4. Alzheimer’s Failures. Sadly, 2018 marked yet another bad year for Alzheimer’s disease drug development. Here are just some of the year’s biggest failures in this area. On January 25, 2018, Takeda Pharmaceutical and its development partner Zinfandel Pharmaceuticals gave up on their five-year Phase III TOMORROW trial after an interim analysis of pioglitazone in mild cognitive impairment due to Alzheimer’s disease. The safety was generally considered fine, but there was inadequate treatment effect. On February 9, 2018, Boehringer Ingelheim indicated it was abandoning its Phase II compound BI 409306 after it failed to meet its endpoints. The drug, a PDE9 inhibitor, being used to treat patients with cognitive impairment and memory dysfunction in schizophrenia and Alzheimer’s, failed to show superiority over placebo in cognition in two separate clinical trials. On February 14, Merck & Company said it was halting protocol 019, its APECS Phase III clinical trial of verubecestat (MK-8931) in Alzheimer’s. An external Data Monitoring Committee (eDMC) had recommended ending it after an interim safety analysis, saying the likelihood of benefits didn’t outweigh the risks. On April 10, vTv Therapeutics announced its azeliragon failed to meet either co-primary efficacy endpoint in its Phase III STEADFAST clinical trial in patients with mild Alzheimer’s disease. On May 18, Johnson & Johnson ’s Janssen division halted its clinical trials of atabacestat, a BACE inhibitor, for Alzheimer’s disease. It was ending the program over safety issues, rather than efficacy. And on September 18, Allergan and Sosei voluntarily suspended clinical trials of HTL0018318 in Alzheimer’s and other types of dementia because of safety issues. #5. Cancer’s Silver Bullet. Researchers from the University of Queensland ’s Australian Institute for Bioengineering and Nanotechnology (AIBN) identified a nano-scaled DNA signature that seems to be common to all cancers. This has the potential to be used as an early cancer detection test, what is often called a liquid biopsy, and if the research pans out, could open up new pathways for universal cancer treatments. Methyl groups are spread across the genome and are implicated in turning genes on and off. The AIBN team found that cancer cells’ genomes often lack methyl groups except for “intense clusters of methyl groups at very specific locations.” The researchers dubbed this “methylscape,” and they observed it in every type of breast cancer they studied, as well as in other cancer types, including prostate cancer, colorectal cancer and lymphoma. “Virtually every piece of cancer DNA we examined had this highly predictable pattern,” stated Trau. “It seems to be a general feature for all cancer. It’s a startling discovery.” #6. Theranos Shuts Down for Good . Nearly three years after the Wall Street Journal first raised questions about the single-drop blood-testing device Theranos claimed would revolutionize the industry, the company closed its doors for good , battered by lawsuits from consumers, as well as the federal government. At one time the high-flying unicorn had a valuation of $9 billion, but after multiple reports revealed the company’s products did not work, the money it so easily raised from Silicon Valley investors began to dry up. Company founder Elizabeth Holmes and former company president Sunny Balwani also face criminal fraud charges that allege the two engaged in a multi-million dollar scheme to defraud investors, and a separate scheme to defraud doctors and patients. Both Balwani and Holmes have entered not guilty pleas to the criminal charges. Holmes agreed to pay a $500,000 fine for fraud to the U.S. Securities and Exchange Commission for earlier charges brought against the two. Balwani is fighting the charges brought against him. The space here doesn’t truly allow for a full re-telling of the Theranos saga, but the story could soon be on the silver screen with Academy Award-winning Jennifer Lawrence set to star in the film as Holmes. The story is reportedly based off of “Bad Blood,” the book written by The Wall Street Journal’s Pulitzer Prize-winning investigative journalist John Carreyrou. #7 . Stressing Gender Diversity . In October, Biotechnology Innovation Organization (BIO) called on its member companies to achieve gender diversity on its boards of directors within the next six years. BIO called for its members to increase female representation at the senior management and leadership level to 50 percent by 2025. For boards of directors, biotech’s biggest trade association called for 30 percent female representation. The call for greater representation came in the wake of other groups within the industry making calls for greater gender diversity. BIO made the move after a second industry party was held during its annual convention over the summer that was deemed disrespectful to women. The annual Party at Bio Not Associated with Bio (PABNAB) included topless dancers who were covered in body-paint that featured the logos of some sponsoring companies. That was preceded by the now infamous 2016 party at the J.P. Morgan Healthcare Conference in San Francisco. Others have also called for more diversity. LifeSci Advisors has been pushing a board training program aimed at female executives. David Lucchino, CEO of Woburn, Mass.-based Frequency Therapeutics , called for greater diversity prior to being named chairman of MassBio (Massachusetts Biotechnology Council). #8. The Opioid Crisis Continues . Opioid-based painkillers have become the poster-child for abuse. Abuse of the drugs has been linked to more than 70,000 deaths annually for the past several years. Over the course of 2018, BioSpace has highlighted a number of lawsuits that have been filed against the opioid-makers by state and local governments. The governments are seeking financial reparations from the companies for the public funds they have spent combatting opioid abuse. The lawsuits almost universally allege the marketing practices used by the opioid drugmakers. Despite the number of lawsuits and the increased awareness of the level of addiction across the country, in November the Food and Drug Administration (FDA) approved a powerful new opioid painkiller called Dsuvia that is reportedly 1,000 times more powerful than morphine. Following an outcry about the approval amid the crisis, FDA Commissioner Scott Gottlieb took to Twitter to defend the decision. Gottlieb argued the FDA should consider the approval of new opioid pain medications that can help fill targeted medical needs. #9. Retractions Rock the Industry . A former Harvard scientist’s name fell into disgrace earlier this year after concerns of falsified data were attached to 31 articles he published in various medical journals. Dr. Piero Anversa was a pioneer in the field of cardiac research. However, some articles that he published in the area of cardiac stem cells have been called into question. Anversa’s work centered on the idea that the heart contains stem cells that could regenerate cardiac muscle. The team claimed that it had identified cells known as c-kit cells that were responsible for that regeneration. Although various teams have tried, the results of Anversa’s work could not be reproduced. As a result, 31 articles he authored have been retracted . There is a growing concern that Anversa’s work in the Harvard lab was fabricated. As a result of the questions over Anversa’s work, Harvard and Brigham and Women’s Hospital agreed to pay a $10 million settlement over allegations of research misconduct involving Anversa and members of his team. Anversa, along with Dr. Annarosa Leri and Dr. Jan Kajstura, used that falsified data to secure funding from the National Institutes of Health (NIH) . Anversa’s lab at Harvard was shuttered in 2015 and none of the researchers currently work for either institution. #10 . Oh, llama . The flu is no joke. Most people are rocked by it in one way or another each year. This year saw the first new flu treatment approved in 20 years by the FDA after Roche snagged regulatory approval for Xofluza . But, this year also marked a new source for a potential flu vaccine that can work on a wide number of flu viruses. Researchers from The Scripps Research Institute were able to harness antibodies from the saliva of llamas and use them as a base for a flu vaccine. The antibodies are diverse camelid single-domain antibodies were used to generate multidomain antibodies with “impressive breadth and potency.” In the study, the researchers used the multidomain antibody MD3606 in mice. They found that the antibody protected the mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. MD3606 could provide protection against most strains of the flu, the researchers said in their abstract. That would be true even if a strain of flu were to change. However, before investing in llama farms as a potential pharma cash cow, the vaccine has not run through human trials yet and it will be years before this research pans out for a potential marketed vaccine.

The most commonly stated statistic about clinical trials is that for every one drug on the market, there are nine that failed. A look back through 2018 indicates there were a great many successes, but plenty of challenges as well. Here’s a look at 10 notable drug challenges of the year. The most commonly stated statistic about clinical trials is that for every one drug on the market, there are nine that failed. A look back through 2018 indicates there were a great many successes, but plenty of challenges as well. Here’s a look at 10 notable drug challenges of the year. #1. Takeda and Zinfandel and Alzheimer’s. On January 25, 2018, Takeda Pharmaceutical and its development partner Zinfandel Pharmaceuticals gave up on their five-year Phase III TOMORROW trial after an interim analysis. They were evaluating pioglitazone in mild cognitive impairment due to Alzheimer’s disease. The TOMMORROW trial was evaluating the genetic-based biomarker risk assignment algorithm (BRAA) in addition to the safety and efficacy of the drug. The safety was generally considered fine, but there was inadequate treatment effect. #2. Boehringer Ingelheim and Alzheimer’s. Unfortunately, Alzheimer’s failures are the norm, rather than the exception. On February 9, 2018, Boehringer Ingelheim indicated it was abandoning its Phase II compound BI 409306 after it failed to meet its endpoints. The drug, a PDE9 inhibitor, being used to treat patients with cognitive impairment and memory dysfunction in schizophrenia and Alzheimer’s, failed to show superiority over placebo in cognition in two separate clinical trials. #3. Merck & Co. and Alzheimer’s. Yes, well, it does seem like a theme. On February 14, Merck & Co. said it was halting protocol 019, its APECS Phase III clinical trial of verubecestat (MK-8931) in Alzheimer’s. An external Data Monitoring Committee (eDMC) had recommended ending it after an interim safety analysis, saying the likelihood of benefits didn’t outweigh the risks. Verubecestat is a BACE inhibitor, a precursor to amyloid-beta. #4. Celgene and Multiple Sclerosis (MS). This particular failure was a bit of a surprise. On February 28, the U.S. Food and Drug Administration (FDA) hit Celgene with a Refusal to File letter over its New Drug Application (NDA) for multiple sclerosis treatment ozanimod. What was surprising was the Refusal to File was over the “nonclinical and clinical pharmacology sections” in the NDA, claiming they were insufficient for the agency to go ahead with the approval process. This was more than a bit unexpected for a company with the reputation and size of Celgene, suggesting that the application wasn’t really ready to go to the agency. Several months later, in June, the company sort of admitted it was their fault, although at the same time, the company’s president of hematology and oncology, Nadim Ahmed , seemed to throw their Receptos unit under the bus, blaming them for the failure. Celgene acquired Receptos in 2015. The NDA for ozanimod was submitted toward the end of 2017, after it reported positive data from the second pivotal Phase III trial, RADIANCE, which was announced in May 2017. On October 10, Celgene reported positive data from two post hoc analysis from the Phase III SUNBEAM and RADIANCE Part B trials, evaluating ozanimod in MS. The company indicates it plans to in 2019. #5. Incyte and Melanoma . On April 6, Incyte Corporation revealed that its IDO1 drug in combination with Merck’s Keytruda did not meet its endpoints in a Phase III melanoma trial. The drug, epacadostat, did not improve rates of progression-free survival in the patient population compared to Keytruda alone. #6. vTV Therapeutics and Alzheimer’s. On April 10, vTv Therapeutics announced its azeliragon failed to meet either co-primary efficacy endpoint in its Phase III STEADFAST clinical trial in patients with mild Alzheimer’s disease. It was made up of two independent, but identical double-blind, placebo-controlled trials, Part A and B. The group in Part A that received the drug showed a 4.4-point decline from baseline in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and a 1.6-point decline from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) compared to declines in the placebo groups of 3.3 and 1.6, respectively. They were not clinically significant changes. Azeliragon is an orally active small-molecule antagonist of advanced glycation endproducts (RAGE). #7. Roche and Exelixis and Colorectal Cancer. On April 11, Roche temporarily halted recruiting patients to its Phase II MODUL clinical trial for metastatic colorectal cancer after four patient deaths. The patients were receiving Tecentriq (atezolizumab) in combination with Exelixis’ MEK inhibitor Cotellic (cobimetinib). Then, in mid-May, the two companies’ IMblaze370 Phase III clinical trial of Tecentriq and Cotellic failed in a comparison to Bayer ’s Stivarga (regorafenib) in colorectal cancer patients who had failed at least two rounds of chemotherapy. #8. Johnson & Johnson and Alzheimer’s. On May 18, Johnson & Johnson’s Janssen division halted its clinical trials of atabacestat, a BACE inhibitor, for Alzheimer’s disease. It was ending the program over safety issues, rather than efficacy. Patients in the EARLY Phase IIb/III clinical trial with preclinical Alzheimer’s disease, as well as a Phase II long-term safety trial, had elevated liver enzymes. EARLY launched in 2015 and was scheduled to wrap in 2024. #9. Sarepta Therapeutics and Duchenne Muscular Dystrophy (DMD). On September 21, the European Medicines Agency (EMA) rejected Sarepta’s application for Exondys 51 for DMD. What is most notable about this was that in September 2016, the FDA approved the drug after a contentious and dramatic battle that involved internal conflict at the agency, media coverage and members of Congress and panels of DMD experts sending public letters urging approval. The application to the EMA was based on two clinical trials in 12 boys with DMD between the ages of 7 and 13. The European agency, in its negative opinion by the Committee for Medicinal Products for Human Use (CHMP), expressed doubts about the evidence, especially related to the studies’ small size, use of historical data, and lack of comparison data beyond 24 weeks. These were essentially the same controversies within the FDA. Meanwhile, Exondys, approved in the U.S., has a yearly price tag, based on the patient’s body weight, of approximately $300,000. #10. Alkermes and Depression—Stay Tuned! On November 2, two FDA advisory committees voted down the company’s NDA for ALKS-5461 for depression. In total, the committees voted 21 to 2 against recommending the drug. They also voted 20 to 3 that the company had not provided substantial evidence that supports the efficacy of ALKS-5461. One of the committee members, Martin Kulldorff , a professor of population medicine and a biostatistician at Harvard Medical School , said, “I don’t think there’s evidence that this drug works.” The drug has had a tumultuous history. The FDA accepted the NDA in April only a few weeks after initially rejecting it due to “insufficient evidence of overall effectiveness for the proposed indication.” In its Refusal to File letter, the FDA said the company would likely have to launch additional clinical trials in order to support a resubmission. But then the FDA changed its mind and Alkermes said it did not submit any additional data to the agency as was originally suggested. The FDA is not required to follow the recommendations of its advisory committees, although with such a strong rejection by two Adcoms, it would be surprising if it did approve the drug. The agency has a target action date of January 31, 2019 for approval.