Today's Top News Thursday, March 10, 2016 | By John Carroll
| | French Health Minister Marisol Touraine |
Why did an experimental "me-too" drug tested in France kill one patient and leave 5 others hospitalized? French health authorities gathered a committee of experts together to explore that question, and their first stab at an answer leaves the mystery largely unsolved. The committee, though, zeroed in on unexpected off-target effects of the drug as a likely culprit for the serious brain damage inflicted on trial subjects. And there were enough visible mistakes in the study--a poor preclinical evaluation of pharmacology, the use of maximum doses that were far higher than what was needed to achieve the desired effect, and erratic dose escalation in the human study--that the authors are calling for new trial rules that should be adopted globally. The drug in question--a painkiller dubbed BIA 10-2474--is an FAAH inhibitor similar to others that have been abandoned; not because they were unsafe, but because they were ineffective. "Its originality is relative as it could appear to be a 'me-too' of several molecules previously developed as FAAH inhibitors such as PF-3845 by Pfizer and JNJ-42165279 by Janssen (J&J)," the scientists report. The Portuguese pharma company Bial had billed the compound as a reversible FAAH inhibitor, but the drug in fact appears to be irreversible. In addition, by blocking FAAH you increase levels of an endocannabinoid called anandamide, which in turn can spur the development of other compounds "which could have a harmful effect, especially on brain circulation." "BIA 10â2474 would appear to be a lot less specific to FAAH than its predecessors," the experts also note, "making binding to other cerebral enzymes plausible." Particularly perplexing for the experts was safety data from studies using the drug on four different species: rats, mice, dogs and monkeys. Several primates were "put down" in the study, but only after taking high doses of the drug. Cerebral damage was noted in rodents, but only after they were given doses more than 100 times stronger than what was planned for humans. In the dogs, though, there were changes in their lungs that raised questions, along with a query about why investigators in the study lowered the dose as they went along. None of that, though, would prevent an investigator from trying the drug in humans, the report states. What was particularly troubling, they said, was that the drug didn't show the kind of efficacy as an analgesic that warranted a human study: "This seems too basic to justify continuing development, a fortiori in humans." Better preclinical pharmacology studies should have been required. The scientists raised questions about some of the patients recruited, including one with a head injury. Dose escalations were sometimes too sharp, and they once again singled out the fact that the investigators continued to dose patients even after one of the patients in the study was hospitalized. Patients in only one of 14 cohorts in the study experienced severe adverse events; "serious central nervous system symptoms exclusively, only appeared in the exposed volunteers from MAD cohort 5 (50 mg). So what could have happened? The scientists speculated that there could have been an interaction with other products; "anandamideârelated toxic effects" could have been involved; toxicity from a metabolite of the drug may have played a role. One favorite theory is that the drug had an off-target effect, hitting other cerebral enzymes, which may have been likely given the random nature of the FAAH inhibition they saw in the drug. And cohort 5 was given doses up to 40 times what was needed to achieve full inhibition of FAAH, raising additional questions about the trial design. The group also wants new rules put in place that govern trial design, which they're recommending for international use. First and foremost, they want to see stricter requirements on preclinical pharmacological studies to demonstrate that a drug has potential. Trial volunteers should be screened better for CNS studies, including a neuropsychological assessment. Maximum doses should be better evaluated and new, best practices rules on dose escalation need to be adopted. - here's the report (PDF) Related Articles:
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Thursday, March 10, 2016 | By John Carroll
The FDA has rescheduled its long-awaited advisory committee review of Sarepta's eteplirsen ($SRPT) for April 25, just 10 days after the third anniversary for the company's claim that the agency was willing to consider an accelerated review of the Duchenne muscular dystrophy drug. Initially slated for earlier in the year, the agency's timetable was upset by a winter blizzard that locked down Washington, DC. Now regulators say they will hold the daylong meeting, which will draw a large crowd of patient advocates, at College Park Marriott Hotel and Conference Center in Hyattsville, MD. Sarepta is now at a new low point after going through a years-long roller coaster ride with its drug. Three years ago, then-CEO Chris Garabedian whipped up investors with a release claiming that the biotech was making real progress in getting the FDA to accept dystrophin production as a surrogate marker that could be used for an early OK. But the data that it was tracking on walking distance among the boys taking the drug were from a tiny study. And an internal review of the drug from the FDA simply dismissed the company's case on efficacy. Earlier this week the biotech reported that it is laying off 30 staffers and consolidating its operations as it awaits the FDA's decision. As of now, the drug has been given little chance of an approval when it comes up for a formal decision. Rival drugs from BioMarin ($BMRN) and PTC Therapeutics ($PTCT) have been shown the door without ceremony, and the harsh agency report on eteplirsen made it clear that the FDA had little use for the data offered by Sarepta. The weather delay, though, did give the agency a chance to push back the PDUFA date, allowing extra time to consider additional data. Patient advocates will come out strong for an approval, regardless of what Sarepta can or cannot prove. And that may be the best card that Sarepta can play right now. There is no treatment option for DMD in the U.S.--PTC's ataluren remains on the market in Europe, despite two failed studies--making this a particularly controversial decision. The PDUFA date is May 26. - here's the notice Related Articles:
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Sarepta snags priority review status to keep pace with BioMarin in DMD race Thursday, March 10, 2016 | By John Carroll
Xoma ($XOMA) investors can finally bid adieu to its lead drug gevokizumab. The Berkeley, CA-based biotech says that the antibody was a bust in early rounds of a Phase III study for pyoderma gangrenosum, and execs now plan to stop all work on the drug and sell it to any willing buyer. What's the drug and the data worth? Not much, judging by its history in the clinic. Last summer the Servier-partnered drug failed a Phase III for Behçet's disease uveitis, and that's after it flunked a Phase II program for erosive osteoarthritis of the hand, ending any shot it had at a broad pivotal study in that indication. The first Phase III crushed the biotech's stock price. But the latest failure, and its decision to finally dump it, was good enough to help push the share price up 16%--good enough to move out of penny stock territory as the company declared a success with its reorganization plan. Xoma recently has axed about 90 staffers, cutting its workforce in half. It gained a $37 million upfront from Novartis in a $517 million deal, licensed out a diabetes program to Novo for $5 million in cash and $290 million in milestones, and sold off a manufacturing center to Agenus ($AGEN). Xoma says it has enough cash on hand--$65.8 million as of the end of 2015--to make it into the first quarter of next year. Its new lead drug is XOMA 358, which is now in Phase II for congenital hyperinsulinism, a rare genetic disorder in which the insulin cells of the pancreas "secrete inappropriate and excessive insulin." "The transformation we initiated in the third quarter of last year--and now have completed in less than six months--was considerable in its scale and complexity, but essential to position Xoma to deliver our promising portfolio of endocrine assets," said Xoma CEO John Varian in a statement. "Novel antibodies and technologies created by XOMA scientists to target diseases such as cancer, diabetes and botulism will be advanced in the capable hands of Novartis, Novo Nordisk, Nanotherapeutics and Agenus, with XOMA sharing in potential successes in certain cases." - here's the release Related Articles:
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Decimated by clinical failure, Xoma turns to plan B Thursday, March 10, 2016 | By Damian Garde
Vericel saw its share value skyrocket Thursday on top-line results for a personalized heart failure treatment, welcome news for a biotech that has toiled for years with little clinical success. The company, formerly Aastrom Biosciences, said its lead pipeline asset met its main goal in a trial on patients with advanced heart failure due to ischemic dilated cardiomyopathy, an orphan disease that results from weakened heart muscles. In the 114-patient Phase IIb trial, Vericel's ixmyelocel-T reduced the total number of deaths and hospitalizations compared with placebo, the company said, while charting a similar safety profile. Vericel didn't disclose detailed results from the trial, saying it plans to present full data at the American College of Cardiology conference next month. The news roughly doubled Vericel's share value, notching a two-year high for the Cambridge, MA, biotech. Ixmyelocel-T is a cell therapy derived from patients' own bone marrow. Vericel uses a proprietary technology to boost the number of stromal cells in patients' marrow to spur the production of anti-inflammatory factors, the company said, creating a personalized therapy Vericel believes can help repair damaged heart tissue. The former Aastrom became Vericel in 2014, moving its headquarters from Ann Arbor, MI, to Cambridge and shifting its focus to regenerative medicine. Months before, the company bought out Sanofi's ($SNY) cell therapy business for just $6.5 million, acquiring three on-the-market therapies. After the transaction, the biotech cut 30% of its staff--about 80 employees--to conserve cash. - read the statement Related Articles:
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Aastrom puts hopes in promising CLI therapy Thursday, March 10, 2016 | By Ben Adams
The FDA has given AstraZeneca's ($AZN) biologics arm MedImmune the thumbs up for an orphan drug status for its rare disease treatment--meaning the biotech may at last soon start to make a dent into the $15 billion paid for it nearly a decade ago. MedImmune's MEDI-551 is currently in mid- to late-stage trials for neuromyelitis optica (NMO)--a rare autoimmune disease that can be fatal. The orphan status is a coveted allowance as it gives greater patent protection for new medicines that can help patients with an unmet medical need. MEDI-551 is a humanized, monoclonal antibody that binds with high affinity to CD19, a protein expressed on a broad range of B cells, including certain B cells called plasmablasts. MedImmune is also studying the drug in a mid-stage trial for patients with diffuse B-cell lymphoma. In NMO, immune system cells and antibodies attack cells in the optic nerves and spinal cord, with its prevalence estimated to be around 5 out of 100,000 people. It primarily affects women and it may be more common in non-Caucasians. There is currently no cure or approved treatment for NMO. MedImmune is currently enrolling several hundred patients into a late-stage, multicenter, multinational, randomized, double-masked, placebo controlled study with an open-label extension period to evaluate the efficacy and safety of the drug. The study is expected to report its first data sets in 2018 and be completed in 2019. Bing Yao, senior vice president of R&D and head of the Respiratory, Inflammation and Autoimmunity Innovative Medicines unit at MedImmune, said: "The orphan designation for MEDI-551 underscores the significant need for an effective medicine for NMO, a rare, devastating disease which causes increasing damage and disability with each attack. MEDI-551 has a unique, targeted mechanism of action offering potential for the treatment of NMO. "We look forward to working with the FDA to advance MEDI-551 to patients suffering from NMO as quickly as possible." MedImmune was bought by AZ in 2007 for an eye-watering fee of more than $15 billion--an amount criticized at the time as the Maryland-based biotech had only a limited number of early-stage pipeline drugs that typically focused around slow-growing flu vaccines and a respiratory drug for children, which turned out to not be so great. AZ said it had its eyes on the future with its purchase but nearly ten years later, little justification has been made for the deal. And in recent years the biotech has to shed hundreds of jobs in California as part of a major restructuring drive for its parent company--a company that has seen its fair share of late-stage disappointments and big changes at the top of its leadership since the MedImmune deal. The biggest victim of AZ's failures was in fact its former CEO David Brennan, the man who signed off on the $15 billion-plus price tag for MedImmune--a decision that many believe was the main factor for his axing in 2012. But since then, MedImmune has racked up the deals and partnerships with other firms and academic institutions--notably in cancer and rare diseases--and this orphan drug status for its new NMO drug is on reflection the most promising thing to have happened for one of its pipeline drugs in years. It's likely not to be seeking marketing approval until the end of the decade given the three-year span of its current trial, but its additional studies for blood cancer could just prove to be the first real tangible revenue producer from the biotech firm. AZ will certainly be hoping so. - read MedImmune's release
- see more on the new study here Related Articles:
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