Assembling my biofolio...
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ACIU/(other AD antibody players) - EP Vantage Interview
[So, obvious question to me is why isn't BAN2401 showing ARIA-E if they're blaming the issue of ARIA-E on IgG1 Mabs and BAN2401 is itself an IgG1 antibody? Does this weaken ACIU's arguments?]
http://epvantage.com/Universal/View.aspx?type=Story&id=748937&isEPVantage=yes
Interview – How AC Immune could finally (dis)prove the amyloid hypothesis
Date November 27, 2017
The failure of just about everything thrown at Alzheimer’s disease so far has not deterred the industry. And last year’s Nasdaq float of AC Immune – which claims to have the broadest Alzheimer’s pipeline in the business – shows that investors, too, remain enthusiastic.
AC’s chief executive, Andrea Pfeifer, insists that the Swiss group really is doing things differently. The keys to success? Accurate diagnosis and the ability to dose patients at high enough levels, she tells EP Vantage. What is more, she reckons she could have foreseen the failures of at least three competing Alzheimer’s projects.
Still, Ms Pfeifer remains an ardent believer in the amyloid hypothesis, and says the problem here is not the target but the lack of a therapeutic window. “[Elan’s] bapineuzumab was highly toxic,” she states, pointing to a high incidence of vasogenic oedema (ARIA-E), which was confirmed as a class effect in an early trial of Biogen’s aducanumab.
Meanwhile, recent setbacks with Merck & Co’s Bace inhibitor verubecestat could have been foreseen given that Bace is involved in amyloid-beta accumulation, so once the protein has formed inhibiting it is useless, Ms Pfeifer says.
“We are not in Bace – this was a very conscious decision,” she says, adding that Bace also suffers from a lack of specificity, hitting 80 proteins in addition to amyloid precursor.
The failure of Lilly’s solanezumab, however, was more mysterious. “I’m convinced that if [Lilly] had given double or triple the dose – which they could have done, because the side effects were pretty minor – I think they would have seen something,” says Ms Pfeifer. “Why they didn’t do it I don’t know.”
Crenezumab and the therapeutic window
AC is perhaps most famous for being the licensor of crenezumab, which along with the Morphosys-originated gantenerumab represents Roche’s two-shot bet on the amyloid-beta hypothesis.
Perhaps less well known is that AC also licensed to Roche the anti-tau MAb RG7345, while its anti-tau vaccine ACI-35 is partnered with Johnson & Johnson. One of its imaging agents, for detecting alpha-synuclein in Parkinson’s disease, is licensed to Biogen.
Diagnostics are a major part of AC’s clinical, if not commercial, strategy, as evidenced by the fact that crenezumab’s pivotal trials require evidence of amyloid-beta in the cerebrospinal fluid to be confirmed by immunoassay or PET scanning.
This points to another failure of competing amyloid-beta-targeting studies, which Ms Pfeifer insists used the wrong population, possibly too broad and definitely too late in the course of Alzheimer’s progression, she reckons: “You couldn’t start early enough because you didn’t have a diagnostic.”
But as well as imaging-assisted early dosing, Ms Pfeifer says you need to have a compound with a decent therapeutic window, which according to her calculations aducanumab, gantenerumab and bapineuzumab might not have.
Why not? Largely because they are IgG1 MAbs, whereas crenezumab is IgG4-based, meaning that it “clears the brain without inflammation. With a mechanism of action on oligomers... it does not attack vascular amyloid-beta. ARIA-E is linked to vascular amyloid-beta perforation.”
Characteristics of selected Abeta-targeting MAbs
Compound Company Isotype Dose* ARIA-E incidence
Crenezumab AC Immune/Roche IgG4 60mg/kg <0.2%
Aducanumab Eisai/Biogen IgG1 3-10mg/kg 35-41%
Gantenerumab Morphosys/Roche IgG1 1.5-17.1mg/kg 10.0-22.9%
Solanezumab Lilly IgG1 5.7mg/kg 1%
BAN2401 Eisai/Biogen IgG1 2.5-10mg/kg 0%
Bapineuzumab Elan/J&J IgG1 0.5-1mg/kg ~10%
Source: AC Immune, scientific papers; *calculated from Clinicaltrials.gov.
To underline her point Ms Pfeifer says AC has dosed crenezumab at 60mg/kg – severalfold higher than competing agents – with no relevant side effects. She says almost all the new competing anti-Alzheimer’s antibodies, though none targeting amyloid-beta, are IgG4s: “I think that’s what our contribution was to the field.”
It is an open question why Eisai/Biogen’s IgG1 MAb BAN2401 has not been associated with ARIA-E, as is the groups’ apparent reluctance to dose higher.
And another intriguing though now hypothetical question is whether bapineuzumab in an IgG4 form would have had a cleaner profile, and could at a high enough dose have shown efficacy (Axovant scraps Alzheimer’s bid – now back to the amyloid hypothesis, September 26, 2017).
Multiple shots
In addition to amyloid-beta AC is targeting tau, with a MAb, small molecule, vaccine and diagnostic. The imaging agent “allows us to discriminate between the different forms of tau”, Ms Pfeifer says, stressing that it is still unclear how many prodromal patients have this protein, or when it develops in the course of disease.
And she thinks only Lilly has tracers to pinpoint amyloid-beta and tau, which if true is surprising given the complexity of Alzheimer’s. “Do we think that with one shot we are going to cure Alzheimer’s?” she asks. “No, it doesn’t work like that.”
While it will be some time before AC’s theories will be proved or disproved – crenezumab’s pivotal trials start reading out in 2020 – Ms Pfeifer is convinced that patient profiling, not genetically but at a protein expression level, is set to grow in importance in Alzheimer’s.
“We are not precise enough,” she says. “You should look at our company as [being in] a situation where oncology was 30 years ago.”
To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter
DNLI (TREM2) -
Of the targets you mention I know most about TDP43 - that's the major dysfunctional protein in ALS and also frontotemporal dementia. A misfolded form of TDP43 called pathologic TDP43 is the major observable brain pathology in ALS. But nobody really knows if the issue is loss of function of the protein (it is used in RNA processing) or whether it is a symptomatic response to something else.
Necroptosis is an alternative cell death pathway different from the more familiar caspase-dependent apoptosis. It involves three kinases - RIPK1, MLKL and RIPK3 of which RIPK1 appears easiest to target. GSK has a RIPK1 compound in trials in IBD, so it has potential applications outside the CNS.
DNLI -
Blocking RIPK1 likely prevent necroptosis of motor neurons
CTMX -
Follow this thread for some opinions on CTMX
FPRX 11/8 CC notes
[Guess not really a surprise that shares rebounded nearly 18% today given the points made in these slides and the CC.]
1. Three independently confirmed responses in heavily pre-treated pancreatic cancer patients (87% third-line or later) without microsatellite-instability (MSI)(anti PD-1 monotherapy is only effective in pancreatic cancer in the <1-2% of patients with MSI). A central read is showing an additional patient having a response moving the total from 3 of 31 to 4 of 31 (13%) with response.
2. None of the grade 5 SAEs were in pancreatic cancer cohort and none occurred in cabira monotherapy arm (only occurred in cabira+Opdivo arm and of type that have been observed with PD-1 inhibitors alone). Later noted in CC that there were 3 patients that experienced these (1.5% of patients) and all occurred in lung cancer cohort and included pneumonitis, respiratory distress, and acute respiratory distress.
3. BMS plans to sponsor a Phase 2 trial in over 100 pancreatic cancer patients soon (will add more than 1 chemo regimen to this combo in this trial to presumably attempt to enhance efficacy). Sounds like this trial will compare the combo alone versus addition of chemo.
4. Patients in this trial later line than those in the registration trial for Onivyde. ORR of 7.7% reported in slides for label for Onivyde registration trial in pancreatic cancer patients. Caller noted that this ORR was recently reported to be a lot higher (15%?) but FPRX wasn't sure if this was an issue of local read as opposed to central read. Also reiterated the point of patients in this trial being later line than those in Onivyde pivotal trial (87% third-line or later versus second line).
5. Sounded like BMS could move up to second line in the upcoming Phase 2 trial but FPRX could not confirm and said to wait for the clinicaltrials.gov entry.
6. Discussion at end of Q&A that the macrophages in pancreatic cancer stimulate fibrosis so if block macrophages with cabira that lead to cold environment this could lead to interesting therapeutic possibilities (relevance to FGEN and/or HALO as well?).
FPRX -
Are you holding any shares? Do you intend to add more or establish a position?
FPRX - additional CC tomorrow (11/8) now -
[Presumably in light of the carnage today, FPRX doesn't want to wait until Saturday for that CC (assuming both will still take place). I hope management has some meaningful clarity to the data to present during this CC.]
Certainly seems disappointing at first blush and I understand the sell-off to some degree. Will be important to hear on the CC on 11/11 if there is some biomarker sub-group that they highlight. E.g., did those 3 PRs occur in a specific pancreatic cancer patient population that they can stratify for going forward?
FPRX is trading down on the SITC poster in pancreatic cancer
FPRX - 3Q17 CC notes
1. In connection with the upcoming SITC presentation on Saturday, 11/11, regarding Phase 1b data for cabiralizumab in combo with OPDIVO, it was noted that there will be an additional call after the meeting to go over the data in more detail.
2. Regarding the initial efficacy that will be presented for one cohort, the CEO said in this CC during Q&A that pancreatic cancer is one indication where it would be easy to show if there is an efficacy signal or not in a trial and whether or not durability of response. [Based on the CEO's response, I'm assuming that it will be efficacy data from the pancreatic arm that will be highlighted at SITC.]
3. CEO also noted that the cohort to be highlighted at SITC enrolled quickly due to a "tremendous unmet need." [This would again presumably point to the pancreatic arm as the one that is likely to be highlighted at SITC.]
FPRX - 3Q17 Results
http://files.shareholder.com/downloads/AMDA-24F834/2580498668x0x962911/329E95A7-39DD-46E9-A19F-46169D2C4BB2/FPRX_News_2017_11_6_General_Releases.pdf
Five Prime Announces Third Quarter 2017 Results and Provides Business Update
SOUTH SAN FRANCISCO, Calif., Nov. 06, 2017 (GLOBE NEWSWIRE) -- Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, today provided a corporate update and reported financial results for the quarter ending September 30, 2017.
"This is an exciting time at Five Prime, as many of our programs are reaching important inflection points," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "Importantly, later this week at the SITC annual meeting, we and BMS plan to report our first clinical data from the Phase 1a/1b immuno-oncology trial studying cabiralizumab with OPDIVO®. The oral late-breaking presentation will highlight preliminary safety, PK and PD data, and initial efficacy from one of the expansion cohorts. We expect all of the cohorts in the trial to be fully enrolled before the end of 2017. Furthermore, we anticipate starting a Phase 1/3 chemotherapy combination trial with FPA144 before year end. The Phase 1 component will serve as a lead-in to our planned global registrational trial of FPA144 as a front-line therapy in patients with metastatic gastric cancer whose tumors overexpress FGFR2b. Additionally, we are on track to file an IND for FPA150, our anti-B7-H4 antibody during the fourth quarter, which would position us to initiate a Phase 1 trial early in 2018.
With the start of 2018, we also look forward to welcoming Aron Knickerbocker as the new president and CEO of Five Prime."
Business Highlights and Recent Developments Clinical Pipeline:
Cabiralizumab (FPA008): an antibody that inhibits CSF1R and has been shown to block the activation and survival of monocytes and macrophages.
- Advanced the ongoing Phase 1a/1b trial of cabiralizumab/OPDIVO® in immuno-oncology.
- Five Prime and Bristol-Myers Squibb (BMS), are evaluating the safety, tolerability and preliminary efficacy of the immunotherapy combination of cabiralizumab with the PD-1 immune checkpoint inhibitor OPDIVO® (nivolumab) in advanced solid tumors, including non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, glioblastoma, renal cell carcinoma and ovarian cancer.
- Five Prime has completed enrollment in some of the Phase 1b cohorts and expects the remaining cohorts to enroll fully during the fourth quarter of 2017.
- Data on preliminary safety, pharmacokinetic and pharmacodynamic data as well as initial efficacy from one of the expansion cohorts that enrolled quickly are scheduled to be presented in a late-breaking oral presentation at the Society for Immunotherapy of Cancer (SITC) meeting on Saturday, November 11, 2017.
- Advanced the ongoing Phase 1/2 trial of cabiralizumab in patients with PVNS.
- Five Prime reported initial trial data at ASCO in June 2017, showing that cabiralizumab demonstrated clinical benefit in patients with PVNS. The company is preparing to enroll additional patients in the Phase 2 portion of the trial to refine the dosing schedule to optimize the therapeutic index of cabiralizumab in this chronic disease setting. These additional data are intended to support a pivotal trial for cabiralizumab in PVNS.
FPA144: an isoform-selective antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) in development as a targeted immuno-therapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family.
- Preparing to start the FIGHT Phase 1/3 clinical trial to test the combination of FPA144 with front-line chemotherapy in patients with metastatic gastric and gastro-esophageal junction cancer. By the end of 2017, Five Prime plans to begin dosing patients in the Phase 1 portion of the FIGHT Phase 1/3 clinical trial in order to test the safety of ascending doses of FPA144 in combination with the FOLFOX6 chemotherapy regimen in unselected patients. This safety lead-in portion of the trial will support the start of the Phase 3 portion of the trial, which Five Prime expects to initiate in 2018. The randomized, controlled Phase 3 trial would serve as a global registrational study and will evaluate FPA144 plus FOLFOX6 versus placebo plus FOLFOX6 in patients whose tumors overexpress
FGFR2b or have FGFR2 gene amplification.
- Applying companion diagnostics to identify the estimated 10% of patients with gastric and gastro- esophageal junction cancer eligible for enrollment in the Phase 1/3 trial. Five Prime plans to use immunohistochemistry (IHC) and circulating tumor DNA (ctDNA) tests to identify eligible patients for its global Phase 3 clinical trial. Five Prime believes the addition the ctDNA test will double the eligible patient population to 10% from the previous 5% identified by IHC testing alone.
- Enrolling patients in Phase 1 safety trial of FPA144 monotherapy in unselected patients with gastric cancer in Japan, where the incidence of gastric cancer is high. Completion of this Phase 1 trial is intended to enable the inclusion of Japanese patients in the planned global Phase 3 clinical trial.
- Closed enrollment of gastric cancer cohorts in the Phase 1 monotherapy trial of FPA144. As Five Prime prepares for the initiation of its front-line Phase 1/3 clinical trial, it has closed enrollment of the gastric cancer expansion cohorts in its ongoing Phase 1 clinical trial evaluating the safety, PK and efficacy of biweekly 15 mg/kg infusions of FPA144.
- Advanced the Phase 1 monotherapy cohort testing FPA144 in patients with metastatic bladder cancer. The company continues to enroll patients in the Phase 1 clinical trial cohort testing FPA144 as a treatment for patients with metastatic bladder cancer whose tumors overexpress FGFR2b, as assessed by the company's IHC test.
- Presenting new data on FGFR2b expression in bladder cancer at SITC 2017. Poster P51, entitled "FGFR2b Expression and Baseline Immune Signature to Guide FPA144 Development in Urothelial Cancer," will be featured in poster sessions on Friday, November 10, 2017, from 12:30-2:00 pm ET and 6:30-8:00 pm ET.
FP-1039: a protein drug designed to block FGF signaling. As a ligand trap, FP-1039 binds to and neutralizes a subset of FGF ligands (such as FGF2), preventing these growth-promoting and angiogenic proteins from reaching FGFR1 on the surface of tumor cells.
- Data from the phase 1b trial in mesothelioma were presented in an oral session at the European Society for Medical Oncology (ESMO) 2017 Congress in September. The Phase 1b trial evaluated FP-1039 with front-line pemetrexed and cisplatin in untreated, unresectable mesothelioma. Five Prime is transferring the process from its former partner, GSK, and developing and a more commercially viable cell line and process; no clinical supply is available at this time. Five Prime is exploring partnering this program.
Preclinical Research and Development:
Continue to advance first-in-class preclinical development candidates in IND-enabling studies.
- FPA150 (anti-B7-H4)
- An antibody designed for two mechanisms of action: to block an inhibitory T cell checkpoint pathway and to enhance killing of B7-H4-expressing tumors by ADCC. B7-H4 is frequently overexpressed in breast, ovarian and endometrial cancers.
- Data featured in an oral poster discussion during the ESMO 2017 Congress suggest that FPA150, which possesses T cell checkpoint and ADCC activity, has the potential to be an effective therapeutic by improving anti- tumor immune responses in patients with cancer.
- Investigational New Drug (IND) application planned for December 2017.
- FPT155 (CD80-Fc)
- A multi-targeting immune modulator that can stimulate T cell responses through three critical pathways: CTLA4 blockade, CD28 agonism (without superagonism) and PD-L1 blockade.
- Preclinical data on FPT155 were featured in a poster presentation at the 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October. Work done in preclinical models with FPT155 suggests that it has the potential to be a potent T-cell co-stimulator with strong antitumor activity, and it may have a synergistic effect when combined with anti-PD1 therapy.
- On track for an IND application in mid-2018.
Target discovered by Five Prime in its respiratory disease collaboration exclusively licensed by partner GSK.
- In August, GSK exercised its right to exclusively license a drug target discovered by Five Prime in the respiratory disease collaboration between the companies. This resulted in a $500,000 payment to Five Prime.
Leadership:
Aron Knickerbocker selected by Board of Directors to succeed Dr. Rusty Williams as President and CEO of Five Prime effective January 1, 2018. Dr. Rusty Williams will be named Executive Chairman.
Bryan Irving, Ph.D. appointed Senior Vice President, Research.
Summary of Financial Results and Guidance:
Cash Position. Cash, cash equivalents and marketable securities totaled $320.8 million on September 30, 2017, compared to $421.7 million on December 31, 2016. The decrease in cash was primarily attributable to cash used in operations to advance FPA144 and cabiralizumab clinical development and preclinical development programs toward IND applications.
Revenue. Collaboration revenue for the third quarter of 2017 increased by $1.6 million to $8.3 million from $6.7 million in the third quarter of 2016. This increase was primarily due to revenue recognized under the 2015 cabiralizumab collaboration agreement with BMS, under which Five Prime is reimbursed for the expenses from the cabiralizumab immuno-oncology trial.
R&D Expenses. Research and development expenses for the third quarter of 2017 increased by $18.8
million to $42.7 million from $23.9 million in the third quarter of 2016. This increase was primarily related to advancing our FPA144 development program and the FPA150 and FPT155 programs toward IND applications.
G&A Expenses. General and administrative expenses for the third quarter of 2017 increased by $0.6 million to $9.7 million from $9.1 million in the third quarter of 2016. This increase was primarily due to accruing rent for the lease on our new corporate office to be occupied in December 2017.
Net Loss. Net loss for the third quarter of 2017 was $43.3 million, or $1.54 per basic and diluted share, compared to a net loss of $19.4 million, or $0.72 per basic and diluted share, for the third quarter of 2016.
Shares Outstanding. Total shares outstanding were 28.9 million as of September 30, 2017.
Cash Guidance. Five Prime expects full-year 2017 net cash used in operating activities to be less than $120 million. The
company estimates ending 2017 with slightly less than $300 million in cash, cash equivalents and marketable securities.
Conference Call Information
Five Prime will host a conference call and live audio webcast today at 4:30 p.m. (ET) / 1:30 p.m. (PT) to discuss its financial results and provide a general business update. To participate in the conference call, please dial (877) 878-2269 (domestic) or (253) 237-1188 (international) and refer to conference ID 95493696. To access the live webcast please visit the "Events & Presentations" page under the "Investors" tab on Five Prime's website at www.fiveprime.com. An archived copy of the webcast will be available on Five Prime's website beginning approximately two hours after the conference call and will be archived and available for replay for at least 30 days after the conference call.
About Five Prime
Five Prime Therapeutics, Inc. discovers and develops innovative therapeutics to improve the lives of patients with serious diseases. Five Prime's comprehensive discovery platform, which encompasses virtually every medically relevant extracellular protein, positions it to explore pathways in cancer, inflammation and their intersection in immuno-oncology, an area with significant therapeutic potential and a growing focus of the company's R&D activities. Five Prime has entered into strategic collaborations with leading global pharmaceutical companies and has promising product candidates in clinical and late preclinical development. For more information, please visit www.fiveprime.com.
TEVA—(-16%)—multi-decade low on weak quarter/newly slashed guidance
Coincidentally (or maybe not) this is an important bug in obesity that I've researched extensively - it's one of the ones that typically re-appears after bariatric surgery. It is my own belief that purple berries (blueberries, blackcurrants, concord grapes) likely increase Akkermansia - they certainly do so in obese rats.
SYRS -
I think this drug is a complete dud. It's a synthetic retinoid analog of ATRA that they're trying to use in AML while "enriching" the population. Problem is that ATRA basically has zero efficacy / use in AML, so there is no meaningful efficacy to enrich.
The other problem is that this is another case of computational strength being used to create biological stratifications without any hard functional data. I don't think the groupings they've identified will provide any meaningful advantage. In a way, it reminds me of GNMX.
All this is supported by the fact that they're already talking about combo studies without having revealed any single agent efficacy data.
Buyer beware.
Betagenon/(Poxel) - AMPK clinical PoC data
Good, if brief, summary of AMPK activation in T2D (Poxel's lead drug is believed to be indirect AMPK activator, and their second drug is indirect AMPK activator for variety of indications).
GNRO - updated P2B post-hoc analysis
[CC on Monday. Appreciate any comments on this PR. Obvious caveats are this is a post-hoc analysis on only 45% of the patients in the trial. But, does anyone see merit in the strong trend (almost stat sig) for the drug on the remyelination front? I guess the data in 1Q18 will go a long way towards answering questions on the merits of this drug, if any.]
http://www.geneuro.ch/data/news/GeNeuro-CHANGE-MS-6m-Data-Presentation-MSParis2017-ENG.pdf
GeNeuro and Servier Announce Promising post hoc Analyses of Six-Month Data from CHANGE-MS Phase 2b Study at MSParis2017
? Anti-inflammatory effect observed in post hoc analysis in active population at 24 weeks for highest dose
? Remyelination effect observed already at 24 weeks for highest dose
? Analysis of full 12-month results expected 1Q18
Geneva, Switzerland, and Paris, France, October 28, 2017 – 11:00 CEST – GeNeuro (Euronext Paris: CH0308403085 – GNRO) and Servier announced today post hoc analyses of 6-month data from the CHANGE-MS Phase 2b study of GNbAC1 for the treatment of patients with relapsing- remitting multiple sclerosis (RRMS). The results showed an anti-inflammatory effect in active patients at the highest (18 mg/kg) of the three doses tested at Week 24. In addition, at the same dose, a promising effect on remyelination was observed at 24 weeks.
GNbAC1 is a monoclonal antibody that neutralizes a pathogenic retroviral envelope protein (pHERV- W Env) encoded by a member of the HERV-W family. CHANGE-MS 6-month results of GNbAC1 were presented today by Prof. Hans-Peter Hartung, chairman of the Department of Neurology of the University Hospital Düsseldorf (Germany) and principal investigator of the CHANGE-MS study at MSParis2017, the 7th Joint ECTRIMS-ACTRIMS meeting. The slides presented by Prof. Hartung are available on GeNeuro’s web site.
The analysis on active patients was conducted on the 121 patients (45% of the patients included), who had at least one gadolinium-enhancing (Gd+) T1 lesion on their Baseline brain MRI scan. A positive effect of GNbAC1 at Week 24 was seen for the highest dose (18 mg/kg) in significantly reducing Gd+ T1 lesions (p=0.008). Similar effects were seen across other MRI measures of neuroinflammation, including new and/or enlarging T2, and combined unique active lesions. The 18 mg/kg dose appeared to consistently outperform both lower doses and placebo across MRI endpoints. These results support the hypothesis of a late onset of action of GNbAC1 seen at 6 months, which could be due to its mode of action through neutralizing a pathogenic protein (pHERV- W Env), without directly modulating or suppressing patients’ immune systems, as well as to the time taken to reach a therapeutic concentration of the antibody in the brain.
Remyelination following treatment with GNbAC1 was measured by MRI with magnetization transfer ratio (MTR) analyses performed in the normal appearing white matter (NAWM) and cerebral cortex of patients. Recent studies have observed that there is a reduction in MTR signal in NAWM and cerebral cortex in patients with MS versus controls, with a pathological gradient of MTR signal loss.
Despite the variability inherent in a 50-center MTR study, the Baseline data reproduced the pathological gradients observed in prior studies. At the highest dose (18 mg/kg), MTR signal increased throughout NAWM and cerebral cortex, from Baseline to Week 24, with statistical trends for GNbAC1 18 mg/kg versus placebo (p=0.06) across each NAWM and cerebral cortical band. The 18 mg/kg dose demonstrated an increase of approximately 2 MTR % units versus placebo, across each NAWM and cerebral cortical band, while placebo had either mild reductions or no change (depending on the specific band observed) through Week 24.
“The effect of GNbAC1 on inflammation and remyelination observations for the highest dose at Week 24 are very encouraging. This is a novel mechanism of action trying to block a potential cause of the disease, so these analyses help us understand how GNbAC1 works in the patient setting and what benefits it could bring to patients. We now look forward to confirmation at the 48-week readout,” explained Prof Hans-Peter Hartung.
“These positive analyses provide additional support to pursue the development of this new approach for patients with MS, in close collaboration with GeNeuro. We are very excited about potentially providing MS patients with a breakthrough therapy,” stated Dr. Christian de Bodinat, Director of Servier’s Neuro-psychiatry Centre for Therapeutic Innovation.
“GeNeuro has undertaken the challenge of developing a new option for treating MS patients, parallel to the existing immunomodulation / immunosuppression pathways, with the ambition to bring new benefits to patients,” stated Jesús Martin-Garcia, CEO of GeNeuro. “The analyses performed show promise, especially in the critical unmet medical need for therapies that promote remyelination. We now look forward to confirming these potential benefits with the final results from this 12-month study, expected in the first quarter of 2018.”
CHANGE-MS Phase 2b study is a randomized, double-blind, placebo-controlled study of 270 RRMS patients in 50 clinical centers in 12 European countries. The primary endpoint is an assessment of the efficacy of GNbAC1 based on the number of inflammatory lesions on brain MRI. Secondary endpoints at 12 months will also include MRI measures of inflammation and neurodegeneration, clinical parameters, and biomarkers, including pHERV-W Env. The protein is thought to be a causal factor of multiple sclerosis, with an impact of inflammation and on the inhibition of remyelination. As announced in August 2017, the initial 6 month data from the CHANGE-MS study failed to reach significance in achieving the primary neuroinflammation endpoint which covered weeks 12 to 24. The analysis of the full 12-month Phase 2b data is expected to become available in 1Q18.
GNbAC1 is a monoclonal antibody which neutralizes a retroviral envelope protein encoded by a pathogenic member of the HERV-W family (pHERV-W Env). Human endogenous retroviruses (HERVs) are ancestral retroviral DNA insertions in the human genome, thought to account for up to 8% of the total. The pHERV-W Env protein is thought to be a causal factor in the development of multiple sclerosis and Type 1 diabetes. GeNeuro is also currently conducting a Phase 2a study in Type 1 diabetes, with results expected during the third quarter of 2018.
Conference call:
Jesús Martin-Garcia, Chairman and CEO and the company management will host a conference call in English, on Monday, October 30, 2017 at 02:00pm CET / 09:00am EDT followed by a Q&A session. Details will be provided on Monday morning.
About magnetization transfer ratio (MTR):
MTR measures the amount of magnetization energy that is transferred from protons that are “fixed” (in tissue) to nearby protons that are “free” (in water molecules), after administration of an “off- resonant pulse” by the MRI scanner. This amount of transferred signal can be measured in each voxel of the MRI scan and, in the white matter of the brain, the MTR signal has been shown to directly correlate to the amount of structural myelin contained within that voxel.
Recent studies have observed that there is a reduction in MTR signal, both in NAWM and cerebral cortex, in patients with MS versus controls. These studies have shown that the amount of structural damage to myelin (as measured by reduction in MTR signal) in otherwise normal appearing white matter and the cerebral cortex of MS patients is worse in people with secondary progressive MS (SPMS) than in people with relapsing-remitting MS (RRMS). This loss of MTR signal is not uniform but occurs with a “pathological gradient” from the surface of the ventricles outward (in white matter) and surface of the brain inward (in the cerebral cortex). Taken together (and along with neuropathological studies showing structural damage to the cerebral cortex of MS patients, which follows a similar pathological gradient), these data suggest a diffusible, pathological factor in the cerebrospinal fluid of MS patients, as the cause of this damage.
About CHANGE-MS
(Clinical trial assessing the HERV-W Env Antagonist GNbAC1 for Efficacy in Multiple Sclerosis)
? Randomized, double-blind, placebo-controlled study of 270 RRMS patients in 50 clinical centers in 12 European countries
? 6-month study with extension up to one year for secondary endpoints
? Primary endpoint: assess the efficacy based on the number of inflammatory lesions on brain
MRI, assessed at the end of the placebo-controlled period
? Secondary endpoints: MRI measures of neurodegeneration and remyelination, clinical
parameters at 6 and 12 months, and biomarkers, including pHERV-W Env
As announced in August 2017, the initial 6-month data from the CHANGE-MS study failed to reach significance in achieving the primary neuroinflammation endpoint which covered weeks 12 to 24. GNbAC1 showed an excellent tolerability and safety over these first 6 months. The analysis of the full 12-month Phase 2b data is expected to become available in 1Q18.
CHANGE-MS is fully funded through the partnership with Servier signed in 2014, in which Servier is involved in the development and potential commercialization of GNbAC1 in MS in territories ex USA and Japan. Under this agreement and depending on achievement of development milestones, GeNeuro could receive a maximum of €362.5M, excluding royalties.
ABBV places bet on “I-N” for AD
Allena Pharmaceuticals is taking the old Altus Drug for Hyperoxaluria and after what appears to be some post hoc analysis is moving it forward.
The founder was the same founder of the technology at Altus Alexey Margolin who successfully took another failed Altus drug (for Pancreatic Insufficiency) started a company and sold it (forget to who) they were approved 2 years ago according to the presentation (but took more than 1 review).
Edit: I think their second drug (for Gout) is also from Altus! I am not sure about Allena now I liked Alexey and the Altus tech. Seemed they got some new IP which would have been a concern.
GBT - 10/23/17 IPF Update CC notes
Just a few from me:
1. Beyond stating that the drug was generally well tolerated in all three arms, the Company said there was no impairment of oxygen delivery in the setting of drug exposures that were approximately twice the highest levels that will be achieved in sickle-cell disease patients (were referring to the 1500mg arm which was highest dose tested in this trial and also highest dose being tested in ongoing P3 SCD trial).
2. Drug exposure in IPF patients is about double that of SCD patients due to the instability of red blood cells in SCD patients. GBT440 is cleared more rapidly in SCD patients because red blood cells are being destroyed by the polymerization process. This does not happen in IPF patients. Drug half-life is 1.5 days in SCD patients and about 3 days in non-SCD patients.
Eisai -
Interesting. I had no idea Eisai owned almost half of $biib #aducanumab
Eisai/(BIIB) - Exercises Option to Co-Promote Aducanumab
http://www.eisai.com/news/enews201760pdf.pdf
FOR IMMEDIATE RELEASE
October 23, 2017
BIOGEN AND EISAI EXPAND EXISTING COLLABORATION AGREEMENT TO DEVELOP AND COMMERCIALIZE INVESTIGATIONAL ALZHEIMER’S DISEASE TREATMENTS INCLUDING PHASE 3 ADUCANUMAB
? Eisai has exercised its option to jointly develop and commercialize aducanumab, with Biogen continuing as development lead
? The expanded collaboration agreement leverages each company’s respective geographic strengths for commercialization and adjusts the respective share of potential profits from potential sales of aducanumab
? Biogen and Eisai will now co-promote Biogen’s multiple sclerosis (MS) treatments, AVONEX ® (interferon beta 1a), TYSABRI ® (natalizumab), and TECFIDERA ® (dimethyl fumarate) in Japan to accounts that Biogen currently does not call upon
Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (NASDAQ: BIIB) (Headquarters: Cambridge, Massachusetts, United States, CEO: Michel Vounatsos, “Biogen”) announced today that the companies have expanded their existing agreement to jointly develop and commercialize investigational Alzheimer’s disease treatments.
Under the terms of the agreement Eisai has exercised its option to co-develop and co- promote aducanumab, Biogen’s investigational anti-amyloid beta (Aß) antibody for patients with Alzheimer’s disease (“AD”).
The expanded agreement leverages each company’s respective geographic strengths for commercialization and adjusts the respective share of profits from potential sales of aducanumab. Biogen will receive 55 percent of the potential profits in the United States and 68.5 percent of the potential profits in Europe. Eisai will receive 80 percent of the potential profits in Japan and Asia (excluding China and South Korea). The companies will have a 50:50 co-promotion split of potential profits in the rest of the world. Further, Biogen will book sales in the United States, Europe, and rest of world markets while Eisai will book sales in Japan and Asia (excluding China, South Korea).
Biogen will continue to lead the ongoing Phase 3 development of aducanumab and will remain solely responsible for all development costs for aducanumab until April 2018. Eisai will then reimburse Biogen for 15 percent of expenses from April 2018 through December 2018, and 45 percent from January 2019 onwards.
Neither party is making any upfront payments associated with the exercise of the aducanumab option. Furthermore, Eisai’s and Biogen’s respective milestone payments under the original agreement for aducanumab and BAN2401, an anti-Aß protofibril antibody, have been eliminated.
The companies will continue to jointly develop elenbecestat* (E2609), a beta amyloid cleaving enzyme (BACE) inhibitor, and BAN2401. The financial terms for elenbecestat and BAN2401 remain unchanged, other than the eliminated BAN2401 milestone payments.
Additionally, Eisai and Biogen have agreed to co-promote Biogen’s multiple sclerosis (MS) treatments, AVONEX (interferon beta-1a), TYSABRI (natalizumab) and TECFIDERA (dimethyl fumarate) in Japan to those accounts that Biogen currently does not call upon.
Eisai will also distribute and book sales for AVONEX, TYSABRI, TECFIDERA and PLEGRIDY® (peginterferon beta-1a) in India and other Asia-Pacific markets (excluding China).
“Through this new agreement, we believe we have improved our ability to maximize the value of aducanumab and expand the potential reach of our industry-leading multiple sclerosis portfolio,” said Michel Vounatsos, Chief Executive Officer of Biogen. “The ongoing collaboration between Biogen and Eisai leverages our respective expertise and strengths in our efforts to bring new treatments to patients and families affected by Alzheimer’s disease.”
Eisai CEO Haruo Naito commented, “Genetic epidemiological studies such as the Icelandic genetic research as well as the knowledge recently gained from various clinical studies such as the aducanumab Phase 1b trial have deepened our conviction in the amyloid hypothesis. We hope to establish a new treatment paradigm for fighting dementia by expanding the strategic collaboration between Biogen, a company that leverages its cutting-edge bio- technology to develop innovative therapies for people living with serious neurological and neurodegenerative diseases, and Eisai, a company which possesses a rich pipeline based on holistic approaches. In accordance with this new paradigm, we plan to further co-develop the collaboration products and hope to advance the world’s potentially first new treatment for Alzheimer’s disease based on the amyloid hypothesis. Through the collaboration and by leveraging each company’s respective strengths in each region, we hope to maximize the benefits for patients and their families.”
DBVT -
All told I think it would be very surprising if the FDA did NOT approve the treatment.
GNCA dumps herpes program—becomes “pure” neoantigen company—40% layoff:
I really don't see how the existence of not of a secondary project should impact the decision about whether to play a binary Phase III or not. Both the up-move and the down-move will be smaller if some value is ascribed to the remaining pipeline - but you can adjust for that by increasing or decreasing your bet.
VSAR -
If you agree with his market analysis, we are talking a 10x return if the drug was successful. And I think all will concede this drug had a much better than 10% shot at success in this non-inferiority trial (which generally are easier than a superiority trial). So that made an investment a reasonable idea on a risk/reward basis.
ASND +37%/AH on VSAR news (eom).
SMMT - raising $15M
[Not sure what to make of the relatively small raise here. As noted in the filing, this won't cover the full cost of P3 trials for ridinilazole. So, not sure if they expect some additional source of non-dilutive capital to come in for the trials or if just expect this to bridge them to another source of dilutive capital.]
https://www.sec.gov/Archives/edgar/data/1599298/000119312517283878/d441728d424b5.htm
Will TRIL be at ASH this year?
Trillium had a little 11% burp up in the last hour so, but I don't see any news.
IF SMMT GOT THIS FROM BARDA SHOULD NOT SYN ALSO GET AT LEAST THE SAME AMOUNT?
GTHX > I don't know if anyone noticed (I'm sure mcbio has!)...but GTHX is up > 100% since Aug 14 on no news that I can find. There has been no twitter chatter or rumors either.
EPIX -48%/PM on termination of EPI-506 program
SMMT - awarded BARDA contract up to $62M
[Has anyone seen a BARDA contract of this magnitude before? This seems like a lot to me. Not sure what the norm is here. Wondering if it speaks to the legitimacy of the opportunity and/or potential prospects for ridinilazole.]
http://otp.investis.com/clients/uk/summit_corporation_plc/rns/regulatory-story.aspx?cid=1575&newsid=923832
Released : 11 Sep 2017 12:00
Summit Therapeutics plc
('Summit Therapeutics', Summit', or the 'Company')
SUMMIT AWARDED BARDA CONTRACT WORTH UP TO $62 MILLION TO SUPPORT THE DEVELOPMENT OF RIDINILAZOLE FOR THE TREATMENT OF C. DIFFICILE INFECTION
Cambridge MA, Oxford, UK, 11 September 2017 - Summit Therapeutics (NASDAQ: SMMT, AIM: SUMM), the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and C. difficile infection ('CDI'), today announces that the Biomedical Advanced Research and Development Authority ('BARDA'), an agency of the US government's Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response, has awarded Summit a contract worth up to $62 million. The funds will support the clinical and regulatory development of ridinilazole for the treatment of CDI, including Summit's planned Phase 3 development program.
Ridinilazole is a highly selective, novel class antibiotic aimed at both treating the initial infection and reducing recurrent disease, which is the key clinical issue in the treatment of CDI. In a Phase 2 proof of concept clinical trial conducted in North America, ridinilazole was shown to be highly preserving of the microbiome of patients compared with the standard of care, vancomycin, and achieved a substantial reduction in rates of recurrent disease.
The Centers for Disease Control and Prevention highlighted C. difficile as one of three pathogens that pose an immediate public health threat. The economic impact of CDI is significant with one study estimating annual acute care costs at $4.8 billion in the United States.
"CDI is a serious public health threat that is a significant burden on the US population, and BARDA has committed to the development of innovative treatments capable of addressing all aspects of this serious illness, including recurrent disease. BARDA's selection of ridinilazole for an award is testament to ridinilazole's promising clinical and preclinical data package that indicate its potential as a front-line treatment of CDI that could reduce recurrent disease," commented Glyn Edwards, Chief Executive Officer of Summit. "This non-dilutive funding award begins to deliver on our strategy of maximizing the value of ridinilazole for patients with CDI, Summit and our shareholders, and we look forward to initiating the Phase 3 clinical program of ridinilazole."
The BARDA contract provides for a cost-sharing arrangement under which BARDA would fund a specified portion of estimated costs for specified activities related to the continued clinical and regulatory development of ridinilazole for CDI. Under the terms of the contract, Summit is initially eligible to receive from BARDA $32 million to fund, in part, obtaining regulatory approval for and commencing enrollment and dosing into Summit's two planned Phase 3 clinical trials of ridinilazole. In addition, Summit is eligible for additional funding under the contract pursuant to three independent option work segments, which may be exercised by BARDA in its sole discretion upon the achievement of certain development and other milestones for ridinilazole. If the three option work segments are exercised in full, Summit would be eligible for an additional $30 million from BARDA. Activities in these three option work segments include the completion of enrollment and treatment in the two planned Phase 3 clinical trials and other activities related to the preparation for the potential submission of application for marketing approval for ridinilazole in the United States.
With this contract award, Summit remains on track to initiate two Phase 3 clinical trials of ridinilazole for CDI in the first half of 2018. The Company continues to explore various funding options for completion of its Phase 3 clinical development program, with these including entering into a collaboration with a third party, equity financing or securing additional non-dilutive funding from government entities and philanthropic, non-government and not for profit organizations.
This project will be funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. HHSO100201600002C.
Summit will file on Form 6-K with the US Securities and Exchange Commission ('SEC') additional information about the agreement with BARDA. A copy of the Form 6-K will be available to download, from the date of this press release, either from the Investors section of the Company's website at www.summitplc.com, or from the SEC website at www.sec.gov.
This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014 (MAR).
VRNA - positive P2A COPD data
[Do you agree that this data is clinically meaningful? For the primary endpoint in particular, how meaningful is the measurement just out to day 3? Is this too soon? For peak FEV1 at day 3, how meaningful is >100ml peak FEV1 over placebo? Also, the PR doesn't say how much greater the average FEV1 is at day 3 compared to tiotropium alone. Red flag?]
http://www.veronapharma.com/blog/verona-pharma-announces-positive-top-line-data-from-phase-2a-clinical-trial-in-copd-with-rpl554-dosed-in-addition-to-tiotropiu-2/
7 September 2017
Verona Pharma Announces Positive Top-Line Data from Phase 2a Clinical Trial in COPD with RPL554 Dosed in Addition to Tiotropium (Spiriva®)
Achieved significant and clinically meaningful additional improvement in peak lung function and faster onset-of-action when added to tiotropium
Demonstrated statistical significance across all primary and secondary efficacy outcome measures, at 6 mg dose; a clear dose response compared to 1.5 mg dose
Management to hold conference call and webcast today at 8 am EDT time / 1 pm BST
LONDON, Sept. 07, 2017 (GLOBE NEWSWIRE) -- Verona Pharma plc (AIM:VRP) (NASDAQ:VRNA) (“Verona Pharma”), a clinical-stage biopharmaceutical company focused on developing and commercializing innovative therapies for respiratory diseases, announces today positive top-line results from its Phase 2a clinical trial, in which RPL554 was dosed in addition to tiotropium (Spiriva®), one of the most commonly used drugs to treat chronic obstructive pulmonary disease (COPD). In summary, despite the limited number of patients, the data from this Phase 2a trial demonstrated significantly improved peak lung function when RPL554 was added to tiotropium in patients with moderate-to-severe COPD.
This was a double blind, placebo-controlled, three way cross-over trial in 30 subjects with COPD and included two different doses of RPL554, 1.5 mg and 6 mg, or placebo, dosed twice-daily for three days, in addition to tiotropium, a long-acting anti-muscarinic (LAMA) bronchodilator, dosed once daily (ClinicalTrials.gov Identifier: NCT03028142). The primary outcome measures for the trial were peak forced expired volume in one second (FEV1) on the third day of dosing and the average FEV1 on the third day of dosing, representing measures of lung function and duration of effect. A number of secondary outcome measures were also recorded. Of note, the 6 mg dose of RPL554 achieved statistical significance, compared to placebo, on all primary and secondary outcome measures. The data confirmed dose dependency between the two RPL554 doses.
Highlights
• Primary outcome measures 1 :
RPL554, compared to placebo, produced a statistically significant (1.5 mg, p=0.002; 6 mg, p<0.001) and a clinically meaningful (>100 ml) peak FEV1 on the third day of dosing (additional bronchodilation) when administered on top of the standard bronchodilator tiotropium (Spiriva®).
Average FEV1 on the third day of dosing (0 - 12 hours) of RPL554 when added on top of tiotropium was larger than that of tiotropium alone (1.5mg, p=0.099; 6 mg, p<0.001).
• Secondary outcome measures:
Both doses of RPL554 produced a statistically significant faster onset of action2 (1.5 mg, 4.2 min; 6 mg, 4.6 min) when added to tiotropium compared to tiotropium alone (37.6 min; p<0.001)
The administration of RPL554 as an add-on treatment to tiotropium caused a marked reduction in Functional Residual Capacity (1.5 mg, p<0.01; 6 mg, p<0.05) and in Residual Volume (1.5 mg, p=0.07; 6 mg, p<0.01), both measures of trapped air in the lung, as compared to tiotropium alone
- Suggesting that RPL554 treatment may reduce dyspnea, a major debilitating symptom of COPD3.
• Both doses of RPL554 were well tolerated as add-on treatments to tiotropium.
Adverse reactions were consistent with previous studies with RPL554 and tiotropium. No cardiovascular-related or gastrointestinal related adverse reactions were reported.
__________________
1 In the study, a p-value<0.05 is regarded as statistically significant
2 Defined as FEV1 improvement by ≥10%
3 Dyspnea (shortness of breath) in COPD patients is often associated with hyperinflation of the lungs resulting from a higher residual volume of air
Dave Singh, M.D., Professor of Clinical Pharmacology and Respiratory Medicine, Medicines Evaluation Unit, University of Manchester and Principal Investigator in this trial, commented, “Top-line results from this Phase 2a study demonstrate the very significant improvement in lung function that can be achieved in COPD patients using RPL554 in addition to tiotropium, the most widely used LAMA treatment. These encouraging results reinforce the potential for RPL554 to provide a meaningful difference in the treatment of COPD patients.”
"We are pleased that RPL554 demonstrated a significant and clinically meaningful improvement in lung function of COPD patients and speeds up onset of action when it is administered as an add-on treatment to one of the most widely prescribed LAMA bronchodilators in these patients. LAMAs are the mainstay of all regimens under the GOLD4 treatment guidelines. We observed a clear dose response with the 6 mg dose, achieving statistical significance on all of the primary and secondary endpoints," said Jan-Anders Karlsson, PhD, CEO of Verona Pharma. "These findings extend our previous data and show that RPL554 has the potential to further improve lung function when administered as an add-on treatment to both short-acting and long-acting bronchodilators. We continue to enroll patients in our Phase 2b study to assess nebulized RPL554 for the maintenance treatment of COPD, and the data from the current study further affirms our belief that RPL554 can become a valuable addition to drugs commonly used by patients with COPD.”
RPL554 is a first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase 3 and 4 designed to have anti-inflammatory as well as bronchodilator properties, and is currently in development for the maintenance treatment of COPD patients and for the treatment of patients with cystic fibrosis.
In previous clinical trials, RPL554 has been observed to result in bronchodilatory effects when used alone or as an add-on treatment to other COPD bronchodilators. These trials have shown clinically meaningful and statistically significant improvements in lung function when RPL554 is added to two commonly used bronchodilators, as compared to the improvements in lung function when either bronchodilator is administered as a single agent. RPL554 has also shown anti-inflammatory effects in a standard challenge study with COPD-like inflammation in human subjects. In these studies, RPL554 has been well tolerated.
____________________
4 GOLD (Global initiative for Obstructive Lung Disease) treatment guidelines - standardized treatment guidelines for COPD based on an assessment of severity of symptoms
Conference Call
Verona Pharma will host an investment community conference call at today 8:00 a.m. Eastern Daylight Time (1:00 p.m. British Summer Time) to discuss the positive top-line data from the Phase 2a clinical trial in COPD disclosed in this press release.
Analysts and investors may participate in the conference call by utilizing the conference ID: 4242325 and dialing the following numbers:
1-877-280-2342 or +1-718-354-1359 for callers in the United States
0800 279 4841 or +44(0)20 3427 1911 for callers in the United Kingdom
0800 589 2674 or +49(0)69 2222 2221 for callers in Germany
Those interested in listening to the conference call live via the internet may do so by visiting the “Investors” page of Verona Pharma’s website at www.veronapharma.com and clicking on the webcast link. Slides highlighting the top-line data are posted to “Events and Presentations” page on the “Investors” section of Verona Pharma’s website at http://investors.veronapharma.com/events-and-presentations/events.
The information contained within this announcement is inside information as stipulated under the MAR. The person responsible for this announcement on behalf of Verona Pharma is Jan-Anders Karlsson, Chief Executive Officer.
About Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease for which there is no cure. The condition damages the airways and the lungs, leading to cough, mucus secretion and shortness of breath, impacting a person's ability to perform daily activities. According to the World Health Organization, COPD is the third leading cause of death globally, with 210 million people worldwide suffering from the disease. Current therapies to treat COPD are aimed at reducing and controlling symptoms. Despite the wide availability of these therapies, many COPD patients continue to suffer acute periods of worsening symptoms known as exacerbations. In the U.S. alone, these exacerbations are associated with approximately 1.5 million emergency department visits, 687,000 hospitalizations, and 129,000 deaths per year. The total annual medical costs related to COPD in the U.S. were estimated to be $32 billion in 2010, and are projected to rise to $49 billion in 2020.
About Verona Pharma plc
Verona Pharma is a clinical-stage biopharmaceutical company focused on developing and commercializing innovative therapeutics for the treatment of respiratory diseases with significant unmet medical needs. Verona Pharma's product candidate, RPL554, is a first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase 3 and 4 that acts as both a bronchodilator and an anti-inflammatory agent in a single compound. In clinical trials, treatment with RPL554 has been observed to result in statistically significant improvements in lung function as compared to placebo and has shown clinically meaningful and statistically significant improvements in lung function when added to two commonly used bronchodilators as compared to either bronchodilator administered as a single agent. Verona Pharma is developing RPL554 for the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis, and potentially asthma.
MGNX - advances first-in-class DARTs
http://ir.macrogenics.com/releasedetail.cfm?ReleaseID=1039211
Sep 5, 2017
Previous Release PDF Add to Briefcase
MacroGenics Advances Two First-in-Class Clinical DART® Molecules
First patient dosed with MGD013 (PD-1 x LAG-3 DART)
IND submitted for MGD014 (HIV x CD3 DART)
NIAID exercises option to advance MGD014 and develop second HIV-directed DART molecule
ROCKVILLE, MD, Sept. 05, 2017 (GLOBE NEWSWIRE) -- MacroGenics, Inc. (Nasdaq: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, today announced the advancement of two of its proprietary bispecific DART product candidates. This progress includes: a first patient has been dosed with MGD013, a DART molecule that recognizes PD-1 and LAG-3; and the submission of an Investigational New Drug (IND) application with the FDA for MGD014, a DART molecule that targets HIV-infected cells and CD3. MacroGenics retains worldwide rights to both of these product candidates.
MGD013 recognizes both PD-1 and LAG-3 and was designed to enable the co-blockade of these two immune checkpoint molecules co-expressed on T cells. MGD013 has a prolonged serum half-life and is being developed for the potential treatment of a wide range of cancers, including both solid tumors and hematological malignancies. MGD013 is MacroGenics' first in a series of product candidates that recognize multiple immune regulator targets as a single recombinant molecule.
MGD014 is a bispecific, Fc-bearing DART molecule that targets HIV-infected cells and CD3-expressing T cells, and is being developed by MacroGenics under a contract awarded in September 2015 by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. NIAID recently notified MacroGenics that it was exercising the first of two options under the HIV contract, funding MacroGenics' advancement of MGD014 into Phase 1 clinical trials as well as the development and testing of a second DART molecule. Under the exercised option, funding of up to $10.8 million is available to MacroGenics for these development efforts. The second option, if later exercised by NIAID, would provide up to an additional $6.3 million for continued development efforts on one or both molecules. Assuming MGD014 IND clearance by the FDA, the Company believes this molecule will be the first clinical bispecific molecule targeting an infectious agent.
"MacroGenics continues to progress its clinical pipeline, and with the recent advancement of MGD013 and MGD014, there are multiple DART molecules being tested in the clinic across multiple modalities and therapeutic areas," said Scott Koenig, M.D., Ph.D., President and Chief Executive Officer of MacroGenics.
Background on Bispecific DART Platform
MacroGenics' DART platform enables the targeting of multiple antigens or cells by using a single molecule with an antibody-like structure. The Company has created over 100 DART molecules which have been configured for the potential treatment of cancer, autoimmune disorders and infectious disease. These DART molecules can be tailored for either short or prolonged pharmacokinetics and have demonstrated good stability and attractive manufacturability.
About MacroGenics, Inc.
MacroGenics is a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases. The Company generates its pipeline of product candidates primarily from its proprietary suite of next-generation antibody-based technology platforms. The combination of MacroGenics' technology platforms and protein engineering expertise has allowed the Company to generate promising product candidates and enter into several strategic collaborations with global pharmaceutical and biotechnology companies. For more information, please see the Company's website at www.macrogenics.com. MacroGenics, the MacroGenics logo and DART are trademarks or registered trademarks of MacroGenics, Inc.
The development of MGD014 is funded in part by NIAID under contract no. HHSN272201500032C.
CLLS—Agree wrt EPVantage's use of the word, disaster, which is hyperbolic, IMO.
SMMT - positive P2 ridinilazole exploratory data vs. fidaxomicin
http://otp.investis.com/clients/uk/summit_corporation_plc/rns/regulatory-story.aspx?cid=1575&newsid=913967
SUMMIT ANNOUNCES POSITIVE TOP-LINE DATA FROM AN EXPLORATORY PHASE 2 CLINICAL TRIAL SUPPORTING RIDINILAZOLE AS A HIGHLY SELECTIVE ANTIBIOTIC FOR THE TREATMENT OF CDI
Ridinilazole treatment more preserving of gut microbiome than fidaxomicin
Oxford, UK, 5 September 2017 - Summit Therapeutics plc (NASDAQ: SMMT, AIM: SUMM), the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection ('CDI'), today announces positive top-line data from an exploratory Phase 2 clinical trial that support ridinilazole as a highly selective and potent antibiotic product candidate for the treatment of CDI. In the Phase 2 clinical trial, ridinilazole preserved the gut microbiome of CDI patients to a greater extent than the marketed narrow-spectrum antibiotic, fidaxomicin. During the trial's ten-day treatment period, ridinilazole treatment had markedly less impact on the gut microbiome of trial patients by measures of overall diversity and changes in key bacterial families, when compared to those trial patients dosed with fidaxomicin.
In the trial, ridinilazole and fidaxomicin both reduced the abundance of C. difficile. However, fidaxomicin-treated patients had reduced abundancy of other bacterial families associated with microbiome health. For a number of these bacterial families, the difference between the two treatments was statistically significant. Another measure of microbiome health is alpha diversity as measured by the Simpson's Diversity Index. There was a greater reduction in alpha-diversity during fidaxomicin treatment compared with ridinilazole-treated patients. These measures were a key secondary endpoint of the clinical trial and provide additional evidence of ridinilazole's precision in killing C. difficile while preserving the gut microbiome. The primary endpoint of the trial was safety, as measured by the number of treatment emergent adverse events and serious adverse events. During the trial, no new or unexpected safety signals were identified and ridinilazole was well-tolerated.
"We increasingly recognise the importance of a healthy and diverse gut microbiome for protection against recurrent CDI, which is a major challenge in the management of the disease. These latest clinical findings show ridinilazole better preserved the microbiome of CDI patients than fidaxomicin, the narrowest spectrum antibiotic currently available for CDI," commented Professor Mark Wilcox, Consultant Microbiologist & Head of Microbiology Research & Development at the Leeds Teaching Hospitals NHS Trust, Professor of Medical Microbiology at the University of Leeds, and Public Health England's Lead on C. difficile in England. "Further, these microbiome data are very supportive of ridinilazole's profile as a highly selective antibiotic with the potential to achieve a meaningful improvement in clinical outcomes for CDI patients."
The exploratory open-label Phase 2 clinical trial enrolled 27 patients aged between 18 and 90 years at trial sites in the US, the UK and the Czech Republic. Patients were randomly assigned to receive either ridinilazole (200mg, twice a day) or fidaxomicin (200mg, twice a day) for ten days. The trial population was unbalanced with more patients randomised to ridinilazole at higher risk of poorer clinical outcomes as measured by ATLAS score, and also with predisposing factors for recurrent CDI.
A secondary endpoint of sustained clinical response ('SCR'), defined as clinical cure at the end of treatment and no recurrence of CDI within the next 30 days, was achieved in seven of 14 ridinilazole treated patients and six of 13 fidaxomicin treated patients. The trial was not designed for efficacy comparisons due to the small number of patients.
Dr David Roblin, Chief Medical and Operating Officer of Summit added, "Ridinilazole is a precision antibiotic that is designed to selectively target C. difficile while being highly preserving of the gut microbiome that plays a crucial role in naturally protecting against recurrent CDI. Ridinilazole has now provided evidence of its high selectivity in two complementary clinical trials. The data from our earlier Phase 2 trial showed a greater microbiome preservation of ridinilazole-treated patients compared with the current standard of care, vancomycin, which led to achieving statistical superiority in sustained clinical response. We believe ridinilazole has the potential to become a front-line therapy for CDI and look forward to initiating Phase 3 clinical trials in the first half of 2018."
More detailed findings from this trial are expected to be presented at an upcoming international infectious disease conference. The results build on positive data from a Phase 2 proof of concept trial of ridinilazole that were published in The Lancet Infectious Diseases in April 2017. Ridinilazole is currently being prepared for Phase 3 clinical trials that are planned to commence in the first half of 2018.
About C. difficile Infection
C. difficile infection is a serious healthcare threat in hospitals, long-term care homes and increasingly the wider community with over one million estimated cases of CDI each year in the United States and Europe. It is caused by an infection of the colon by the bacterium C. difficile, which produces toxins that cause inflammation and severe diarrhoea, and in the most serious cases can be fatal. Patients typically develop CDI following the use of broad-spectrum antibiotics that can cause widespread damage to the natural gastrointestinal (gut) flora and allow overgrowth of C. difficile bacteria. Existing CDI treatments are predominantly broad spectrum antibiotics, and these cause further damage to the gut flora and are associated with high rates of recurrent disease. Reducing disease recurrence is the key clinical issue as repeat episodes are typically more severe and associated with an increase in mortality rates and healthcare costs. The economic impact of CDI is significant with one study estimating annual acute care costs at $4.8 billion in the US.
About Ridinilazole
Ridinilazole is a small molecule antibiotic that Summit is developing for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a targeted spectrum of activity that combined a potent bactericidal effect against all clinical isolates of C. difficile tested with minimal impact on other bacteria that are typically found in the gut microbiome. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response ('SCR') rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. Ridinilazole, an orally administered small molecule, has received Qualified Infectious Disease Product ('QIDP') designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.
About Summit Therapeutics
Summit is a biopharmaceutical company focused on the discovery, development and commercialisation of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programs focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection. Further information is available at www.summitplc.com and Summit can be followed on Twitter (@summitplc).
MGNX -
My question to both of you - do you think that 4/8 patients is correct or should be rather 4/38 patients? the latter conforms to the their prior format. Also, they later list exactly 4 patients... could they have just madea typo and meant 4/38? It seems important.
MGNX -
The number of =>G3 tox events gave me pause, though. What about you?
MGNX -10%/AH—JNJ abandons Duvortuxizumab collaboration