Today's Top News Tuesday, March 22, 2016 | By John Carroll
 Eli Lilly ($LLY) didn't just surprise investors with its sudden about-face last week on its long-running Phase III program for the Alzheimer's drug solanezumab. Some investigators with years of experience in the field have been puzzling out the move to downgrade function from a co-primary to a secondary endpoint, even though daily function and improved cognition remain a required combined feature for any pivotal trial design approved by regulators on both sides of the Atlantic.
The bottom line is that Lilly clearly thinks its drug--which failed two earlier late-stage studies only to see Lilly double down, convinced that a second look at the data pointed to a clear clinical pathway that would lead it to one of the Holy Grails of drug research--is going to fail at significantly improving function. Facing the prospect of a repeat, high-wire flop for another one of its pricey home run swings, executives decided to retreat to cognition, hoping that the data would be good enough to argue the issue with regulators, who will be feeling the heat from patients and advocates with no truly effective therapies to turn to. "None of us have liked the co-primaries," says Dale Schenk, the CEO of Prothena and former CSO of Elan, which handed bapineuzumab over to J&J and Pfizer. (It failed in another big Phase III.) In Lilly's case, adds Schenk, who's not directly involved in Alzheimer's research currently, there is supportive data to suggest their drug is having a clinical effect. Timing may be a factor as well. But it's not even close to a sure thing. Many of the clinicians in the field would far prefer to see an improvement in function, Schenk adds, with practical evidence that patients are better able to care for themselves day to day, than in cognition, where there's likely to be less agreement on the significance of an observed improvement as "different parts of the brain do different things." The FDA has modified its position, signaling to developers a couple of years ago that regulators would be more flexible in their consideration of new drugs. But this move still marks a definite stretch. "I, like my colleagues, who have worked in the AD space, especially around development of disease modifying therapies, are very surprised by the announcement in the change in primary endpoint for Expedition3," notes Enchi Liu, who worked on the bapineuzumab Phase III during a stint at Janssen, in a message to me. "We all know the requirement for a co-primary of cognitive and function to gain approval, and in addition if a disease modification claim is sought that additional supportive data will be required to show that the underlying disease processes has been directly impacted (eg effect on a biomarker). "The only guess I have about their move is that there has not been a successful AD program since the last approval for memantine and they are betting on negotiating an approval based on a single primary cognitive endpoint since they will be the first to file after the negative readout of bapineuzumab in 2012. Perhaps they will also use the fact that solanezumab has an effect on cerebrospinal fluid Abeta. So I'm not sure if this will hurt them; they are certainly making a bold move." If Lilly is successful in getting the FDA to significantly lower the bar on efficacy for Alzheimer's, that kind of move could have a major impact on a variety of programs, including drugs like gantenerumab, which failed for Roche, or crenezumab and possibly even Biogen's closely watched program for aducanumab. "It will be very interesting for us and the industry globally, to see how the regulators in the different countries will respond to Eli Lilly's amendment submission to demote the functional endpoint ADCS-iADL to a secondary endpoint in their EXPEDITION 3 study," says Andrea Pfeifer, the CEO of AC Immune, partnered with Genentech on crenezumab, now in Phase III. "As you state in your email, current regulations (eg the recent EMA draft guidance issued for public consultation only last month) for studies in patients with Alzheimer's disease which has progressed to the point where there is an established dementia (as in Lilly's Expedition 3 study) DO require BOTH cognitive and functional outcome measure to be declared as primary endpoints in pivotal studies and to be positive for drug approval." "The topic of which endpoints to best use at the different disease stages (prodromal, mild and moderate dementia etc) is a widely discussed one in the industry and with regulators." That buzz just got louder. And little of it sounds cheering for the Alzheimer's team at Lilly. -- John Carroll (email | Twitter)
Monday, March 21, 2016 | By John Carroll
 | | UCLA's Perry Shieh |
Sarepta ($SRPT) enjoyed a rare spike in its share price today after several dozen experts in Duchenne muscular dystrophy, including a host of site investigators and advisers working on the drug, circulated a detailed letter explaining why the FDA should support the company's application for eteplirsen--despite a withering internal assessment from agency insiders. On a point-by-point basis these physicians took exception to the FDA review, noting that despite the extremely small number of patients in the key study--with data on only 12 boys--their experience observing patients in their practices suggest that the drug was clearly effective. As news of the letter spread, Sarepta's share price surged 20%. "The collective signatories note that the group of 12 eteplirsen treated boys, even accounting for daily deflazacort usage or twice-weekly prednisone, is clearly performing better than our collective clinical experience and the published literature would predict," the lineup of physicians asserts. "Collectively, a portion of us represent a group of physicians who have observed over 5,000 DMD patients in our practices over an average of more than 15 years. Published external natural history data and our clinical experience strongly support that the 12 boys treated for over 4 years show a milder clinical progression, likely due to a positive treatment effect of eteplirsen." A quick check of Sarepta's websites and online records also revealed that many of the as-advertised experts have close ties to Sarepta, often listed as the very investigators who have been helping Sarepta gather the controversial data together and analyze it for regulators. Among those who have worked on drug trials related to eteplirsen and signed the letter are UCLA's Perry Shieh (a principal investigator for one study), Stanford's John Day (who lists Confirmatory Study of Eteplirsen in DMD Patients on his resume; and Kathy Mathews at the University of Iowa (a hub site investigator and principal). Harvard Med School's Louis Kunkel and the University of Washington's Jeff Chamberlain, who signed on to the company's advisory board, are also signers on the lobbying letter, along with many trial site leaders, including Anne Connolly, Susan Apkon, Nancy Kuntz and Basil Darras, all listed on Sarepta's website. Dr. M. Carrie Miceli and Dr. Stanley Nelson, co-director of the Center for Muscular Dystrophy at UCLA, took the lead on the letter, which was dated February 24 and addressed to Dr. Billy Dunn, director of the division of neurology products at the FDA. The wife/husband team launched a public campaign advocating for new drugs to be approved for Duchenne, which afflicts their teenage son. Miceli, Nelson and Chamberlain also sit on the advisory board of CureDuchenne, an advocacy group which has offered its full-throated support of eteplirsen's approval, along with Sarepta CEO Ed Kaye. In their view, which you can see here, the best approach would be to go ahead and approve eteplirsen and then go ahead and let upcoming data provide confirmatory results. "The FDA Briefing Document also implies that the ongoing non-placebo controlled confirmatory eteplirsen trial (NCT02255552) and additional eteplirsen safety studies (NCT02420379 and NCT02286947) initiated in response to FDA guidance may not be considered sufficiently robust to allow for approval," the letter reads. "Given the relative paucity of patients with amenable mutations, the flexibility afforded by FDASIA, and the fact that many of the boys between the ages of 4 and 21 years with relevant mutations are already receiving eteplirsen in the context of these trials, it would be difficult to conduct a large placebo controlled study in the near future. Thus, it would be dubiously ethical to veer from the currently recommended study path at this point. In keeping with the criteria imposed by FDASIA for accelerated approval for rare disease with unmet need, we conclude that the aggregate data, described in the briefing documents, are providing substantial evidence of efficacy and use in the greater population of boys amenable to exon 51 skipping is appropriate. We suggest that the most scientifically robust way forward and the most ethical choice for the Duchenne community is in the context of an accelerated approval followed by a confirmatory trial." Just how persuasive this group can be, with such close ties to Sarepta, won't be clear until April 25, when the FDA's advisory committee will finally meet for a review. The FDA's internal assessment virtually dismissed Sarepta's case. But the biotech has enjoyed intense support from parents and patients--as well as the professional community, which has played a big role in testing the drug. Related Articles:
Sarepta has a new date with an FDA AdComm for Duchenne drug eteplirsen
Sarepta shrinks as execs wait for FDA's decision on Duchenne drug
Sarepta faces another FDA delay with its much-scrutinized DMD drug
Sarepta shares crash on a harsh FDA review of Duchenne's drug Tuesday, March 22, 2016 | By Ben Adams
 | | CEO Werner Lanthaler--Courtesy Evotec |
German firm Evotec has spun off its first drug unit as it looks to start a new era in its business strategy. The Hamburg-based company, which runs CRO-like services alongside drug discovery projects, has named the new early-stage firm Topas Therapeutics GmbH, which is an abbreviated form of "tolerizing particles"--the main process behind the new firm's platform. Topas, which will also be based in Germany, will specialize in the field of nanoparticle-based therapeutics to treat immunological disorders. The new company starts life with a €14 million ($15.7 million) Series A funding injection from Evotec (which also holds a major equity stake in Topas), as well as from Epidarex Capital, EMBL Ventures and Gimv. It emerges from the neuro portfolio of Bionamics GmbH, which was acquired by Evotec back in 2014. Topas' lead program is in multiple sclerosis (which it believes could prove disease-modifying and therefore very lucrative) and is set to enter the clinic in 2017. The drug will be developed by its proprietary liver-based tolerance induction platform--a platform exclusively licensed from the University Medical Center Hamburg-Eppendorf, where it was invented by Johannes Herkel, Jörg Heeren and other colleagues in Hamburg. In a statement, Evotec said its spinoff intends to develop its MS program through to proof-of-concept, after which licensing partners will be sought. Topas has been billed as Evotec's first spinoff and as a new model for the company--although ten years ago it did in fact raise €25 million for Evotec Neurosciences (ENS), a unit the company called a "subsidiary" but looked and felt a lot like a spinoff. Whatever it may have been, it was shortly re-bought and subsumed back into Evotec. Evotec says that there is a potential for further spinoffs "as this is an additional tool that fits very well" as an extension to its EVT Innovate program--a network of academia, pharma and biotech that links on drug discovery. This network will likely prove very helpful when developing new funding streams for Topas in the future. The Bionamics deal and the creation of EVT Innovate was the beginning of a change in Evotec's business model, which had historically focused on risk-splitting projects with Big Pharma sponsors, in which the company often handles development of an external candidate in exchange for CRO fees and a cut of future profits. That model has attracted partners including Bayer, Boehringer Ingelheim and Johnson & Johnson ($JNJ), but with this new spinoff, the company is expanding to include a more bottom-up approach to drug development. Topas will be led by Dr. Timm Jessen, who was formerly MD of Bionamics and served as the CEO of Evotec for 7 years. Dr. Werner Lanthaler, CEO of Evotec and interim chairman of the supervisory board of Topas, told FierceBiotech the spinoff was part of an evolution of his company (which he points out is short for "evolutionary biotechnology") and has been incubated for the past three years after its purchase of Bionamics and the growth of EVT Innovate. "Topas specifically has required a new type of thinking to be created, and this has come from our Innovate project and our other programs. We have been breeding Topas, together with the three founders of Bionamics, over the last 2-3 years. Now, we're looking at a clinical entry for 2017 [for its lead MS candidate]--this of course has not happened over night, but is a result of an integration into the Evotec business model over the past few years." Its lead drug has been under preclinical testing but there is a big jump to human trials--it also has the added pressure of being the great white hope for the entire Topas company. Lanthaler, however, believes the drug will perform: "For Topas to come into existence, it needed to convince us that its platform could produce good data, otherwise it never would have happened. "We know of course that the MS market is not competitive-free, and to even think about starting something like this you need to know you have better data than what's already out there. The platform is very well tailored towards this drug and other targets and is a very elegant way of going into the liver and producing the best results." But Evotec is of course not the only company putting in money as it has gained funding from external sources. "We know this is a high risk area which is why it was prudent to not only take Evotec money but also an investment consortium to take things forward," Lanthaler explained. "This gives us an optimal risk-reward profile." He said that future spinoffs have not been confirmed, but is open to the idea of more as part of its evolving business model. "We don't commit ourselves to 'X' number of spinoffs in the future--that would be stupid--but just creating the format and the concept opens up the possibility of other firms to talk to us. And of course doing this can also help us leverage our platforms with external money." Topas will be led by Dr. Timm Jessen, who was formerly MD of Bionamics and served as the CEO of Evotec for 7 years. Lanthaler said Jessen's return to the company was one of the reasons why Topas could be launched: "Here with Jessen we have a guy who knows our platforms and our systems, and who I recruited back to Evotec [after the 2014 Bionamics buy]. You want someone like that to run things when you're spinning off a company." Meanwhile, the company also announced its financial results for the year today, with group revenue growth of 43% to €127.7 million, with adjusted group EBITDA in 2015 amounting to €8.7 million. Lanthaler said of the results that "We are on full speed and have great traction." - read the release Related Articles :
UCB taps Evotec to pitch in on drug discovery
Evotec posts 50% growth with a big year in sight
Evotec partners up for rare disease R&D in a discovery deal Tuesday, March 22, 2016 | By John Carroll
 | | Jan van de Winkel |
Genentech and Johnson & Johnson ($JNJ) are joining hands on another checkpoint combo program, matching Darzalex (daratumumab) and the PD-L1 drug atezolizumab for an unidentified solid tumor as well as multiple myeloma, where Darzalex is already approved for use. J&J will take the lead on a Phase Ib combination study for a solid tumor, while Genentech will be in charge of the multiple myeloma program, which is already in the clinic. Roche's ($RHHBY) atezo has lined up as the first likely approval for the PD-L1 (programmed death ligand-1) side of the checkpoint equation for cancer, following breakthrough approvals for Merck's ($MRK) Keytruda as well as Bristol-Myers Squibb's ($BMY) leading drug Opdivo, both PD-1 drugs. The class has demonstrated a distinct ability to dismantle a cloaking device cancer cells use to escape detection by the immune system, opening up a broad based assault that can be easily matched with more targeted therapies. The industry has followed up with dozens of combination development programs, and J&J and the big Roche subsidiary will now take their place in a very long line. At one point last year Roche had three dozen ongoing trials for atezolizumab, including 11 Phase III studies. All the leaders, including a more distant fourth-place rival at AstraZeneca ($AZN), have been pouring in money and resources in an effort to identify and capture key market segments in the oncology field. Just days ago Roche and Kite ($KITE) unveiled plans to combine atezo with a leading CAR-T therapy, which engineers T cells into attack vehicles. That closely followed the FDA's decision to grant atezo--already named a "breakthrough" therapy--a priority review for bladder cancer. And Pfizer ($PFE)/Merck KGaA have been ramping up their combo plans in the checkpoint field as well, recently allying itself with Verastem's failed therapy. The partnership news today is also good for Genmab, which outlicensed the CD38 antibody Darzalex to J&J. Darzalex was approved last fall to treat multiple myeloma. "We are very excited about the start of the first study to investigate daratumumab in a solid tumor, potentially expanding its clinical utility beyond hematological cancers," said Jan van de Winkel, chief executive officer of Genmab, in a statement. "We are equally excited about testing daratumumab in combination with an immune checkpoint inhibitor, such as Roche's anti-PDL1, atezolizumab, in multiple myeloma. Both studies mark a key next step in the expansive clinical development of daratumumab in the hope to find even more effective treatment options for cancer patients." - here's the release Related Articles:
Roche, Kite Pharma sign CAR-T and PD-L1 combo deal
Roche's new PD-L1 bladder cancer drug could be on the market by September
J&J nabs an early OK for 'breakthrough' multiple myeloma blockbuster contender Darzalex
J&J positions blockbuster contender daratumumab for a multiple myeloma showdown
Genmab continues upward march as J&J starts quick-fire rolling submission
J&J builds promising case for multiple myeloma competitor daratumumab Tuesday, March 22, 2016 | By Ben Adams
New York biotech Syntimmune has hit its targets in preclinical testing and been given a $10 million gift for its efforts. The autoimmune disease specialist that works under a virtual model achieved preclinical proof of concept and hit its preclinical safety testing targets, triggering a second $10 million tranche from its $26 million Series A financing pot. The NY-based firm, which launched only two years ago, is seeking to develop novel treatments for IgG-mediated autoimmune diseases via its first-in-class lead candidate SYNT001. The Series A financing has been co-led by Apple Tree Partners and Baxalta Ventures, the corporate venture capital arm of soon-to-be-acquired Baxalta ($BXLT), with participation by the Partners Innovation Fund and additional investors. The $10 million will be used to complete a Phase 1a clinical trial in healthy volunteers of SYNT001. Syntimmune said in a statement that it intends to submit an IND application to the FDA for the drug in the second half of the year so it can start human testing in 2016. Laurence Blumberg, founder, MD and COO of Syntimmune, told FierceBiotech it's achieved a lot in just a few years: "We're a bit further along than a nascent startup, so it's a bit misleading as we look very young as we've finally just now shared something about the company--but we've made remarkable progress since 2013. "We've raised a lot of money and we were lucky in some ways as the funding environment back in 2013/14 [during the Series A funding round] was a lot more conducive than it is today, and we were right to take advantage of that healthy financing market, because a lot of early-stage biotechs are suffering." But why autoimmune disease? Blumberg explained: "This type of biology we've thought about for 20 years and now we've found a new and important way to use these targets. And autoimmune disease is a big, unmet need and what we're focusing on--IgG--becomes pathologic and affects people across a major range of diseases, from orphan diseases to more common conditions. The treatments out there for these diseases are suboptimal. Most are treated with plasma exchange which is a really invasive therapy that involves having blood removed and then put back into a patient. "We know a lot of people are thinking about this target and it's at the point where it's well validated and ready for trials. We have the team to push this forward better than anyone else as we house the international thought leaders on this target." This includes the scientific founder of the firm, Laurence's brother Richard Blumberg, who is co-director of the Harvard Digestive Diseases Center and Director of the Brigham Research Institute. But what about the future--will Blumberg seek a Big Pharma buyout? "You don't build these companies to sell them," he said. "The challenge for us however is that this is not something we can fund ourselves indefinitely. We have a strong investor base but there is a lot you can do with a drug like this--and we think it will be a major blockbuster--from ultra-orphan indications to orphan indications. And after a while it will become too big for even the best capitalized biotech to continue on independently. So we may indeed look for a partner one day if there is the opportunity and the need but right now, it's not on the cards as we have the money we need for this stage of development." He says there may also be a float in the future, but that the "breadth of the opportunity from our platform will dictate what we do." The firm said it also has two additional, earlier-stage therapeutic programs targeting other unique aspects of FcRn biology. FcRn is a central mediator of IgG-related immunity and part of an important pathway that enables abnormal IgG responses in a large number of clinical settings, including autoimmune disease. There are currently no commercially available therapies designed to block IgG-FcRn interactions, which underlie diseases that affect multiple organ systems and for which there are continuing substantial medical needs, such as inflammatory bowel disease, lupus erythematosus, dermatomyositis and others. - check out the Syntimmune release Related Article:
Baxalta, on cusp of buyout, bags cancer drug deal with Onconova  | 
@FierceBiotech: Duchenne docs--AKA Sarepta investigators, advisers and advocates--back controversial case for eteplirsen.