I agree that 809+ kalydeco and 661 # kalydeco is superior to just kalydeco. 661 has benefits over 809 and is the future and then the third gen correctors added. But the results show very similar benefits between 661 and 809 so given that 809 is the now, and I think it would get residual function on label at least one year earlier, why not do a phase three now with 809 at the same time as the 661. Vertex would have to do a kalydeco arm because residual functions benefit from kalydeco alone as well...but either way you'd have on label.
So I agree re the future, but am I missing something for why another quick study wouldn't save a year and get another 200 million for that one year being worth the cost to vertex?
in my interpretation of all available data VX-661 is superior to lumacaftor. On approval of 661 lumacaftor will become obsolete. Or do you see patients that will benefit more from luma than from 661? The future is ivacaftor+661 and iva+661+second gen corrector.
So in my view VRTX ought to focus on 661 and negotiate with FDA on as little as possible extra trials for lumacaftor.
1. Is the FDA requiring you to add a mono arm to the 661 combo study for ddf508.
2. With results for the 6-11 study for Orkambi scheduled for October, what is the timeline for submission of sNDA and approval?
3. Are you (and if not, why not) doing a Phase 3 for Orkambi for residual function mutations.
Re #3. here's my reasoning. What am I missing? There are 3000 in US/EU/AU with residual function mutations. Phase 2 proof of concept shows Kalydeco works and the 661/combo shows further improvement for those with 551 and df508. 661 and 809 work with the same mechanism, so why not do a Phase 3 study with Kalydeco, Orkambi, and Placebo for residual function. With both Kalydeco and Orkambi (by then) approved, it'd likely save a year by doing an sNDA (as oppose to waiting for 661 study completion and approval), to expanded the label for either Kalydeco or Orkambi. There were only 500 R117 CFers but Vertex did a 70 person Phase 3 and got an expanded label for them. The residual function mutations currently have no basis for on-label use. In the U.S. alone, that triple the size of R117, or more than double if you subtract the 300 in the 661 study and any open label use following a Phase 3 study of Kalydeco/Orkambi. Even if its only 1 year, that access to CFers for the year and likely $200 Million more for Vertex. (1000 x 200K). Thoughts?
NORWOOD, MA -- (Marketwired) -- 05/18/15 -- Corbus Pharmaceuticals Holdings, Inc.(CRBP) ("Corbus" or the "Company"), a clinical stage drug development company targeting rare, life-threatening chronic inflammatory and fibrotic diseases, announced today that its Investigational New Drug ("IND") application to the U.S. Food and Drug Administration ("FDA") is now open and the Company is authorized to initiate a Phase 2 clinical study with Resunab™ for the treatment of cystic fibrosis ("CF"). Corbus expects to initiate a Phase 2 clinical study with Resunab in adults with CF within the next 90 days.
CF is a chronic, life-threatening, genetic disease that primarily affects the lungs and digestive system. CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. In the lungs, the abnormal protein causes the buildup of thick, sticky mucus which, in turn, leads to recurrent bacterial infections, chronic inflammation and pulmonary fibrosis. Individuals with CF have an exaggerated, yet ineffective, innate immune response that compounds the inflammation and lung damage caused by the infections. The outcome is relentless, harmful inflammation leading to progressive lung damage and eventual failure impacting both the quality and duration of life.
Resunab is a novel synthetic oral drug that has the potential to treat the chronic pulmonary inflammation and fibrosis associated with disease progression in CF, regardless of an individual's specific CFTR gene mutation. Corbus recently received a $5 million development award from Cystic Fibrosis Foundation Therapeutics ("CFFT") to support the Company's Phase 2 clinical trial of Resunab for the treatment of CF.
"The CFFT, European Cystic Fibrosis Society, and key investigators provided expert and invaluable advice on the design of our Phase 2 CF study, and we are grateful to them for this assistance. With their help, we are pleased to have achieved this important regulatory milestone for our clinical development program," stated Barbara White, M.D., Chief Medical Officer of the Company. "The existing clinical safety data, as well as the pre-clinical efficacy data, points to the potential for Resunab to provide therapeutic benefit to CF patients. We believe that Resunab could potentially improve the clinical outcome for individuals with CF and favorably impact their lives."
"Based on its novel mechanism of action that turns on the resolution of the inflammation pathway, Resunab has the potential to treat the chronic lung inflammation and fibrosis at the root of the morbidity associated with CF," added James Chmiel, M.D., M.P.H., co-principal investigator of the Phase 2 study, specialist in pediatric pulmonary diseases in the Division of Pediatric Pulmonology, Allergy, Immunology and Sleep Medicine and Associate Director of the LeRoy W. Matthews Cystic Fibrosis Center at University Hospitals Rainbow Babies & Children's Hospital. "I believe Resunab has encouraging potential as a novel therapy for CF and look forward seeing its potentially life-changing outcome for individuals with CF."
Verity, I only meant using one's own 508 CFTR as a template to replace the other CFTR on the other allele. They could do this kind in animals, but not for CFTR. They could also deliver normal pieces by attaching them to modified lentivirus. The compound has to be inhaled, I suppose.
Could you explain why it will be easier to make hetero homozygous? Won't they have a template for wild type cftr? Or do you mean having wthe individuals very own cftr allele to use as a template? If so, would they be able to use carrier parents templates for homozygotes? I.e. I have one normal gene and one df508 ..ds got the bad gene. Could they use my other good one as the template to make his one bad one good with crispr in the way you mean re the template...
A positive Ib result could shot up the stock. We are talking about pancreatic, ovarian, glioblastoma multiforme, NSCL cancers and other ALT dependent tumors.
Immune therapy, PDL-1 and other kinase drugs improve survival by 3 months - 9 months and not truly meaningful survival drugs and are approved for advanced disease. VX 970 if works and has acceptable safety profile, will be used with first line topoisomerase 1 inhibitors and I consider this drug as " VRTX Avastin."
If I am buying VRTX at this level, it is because of VX 970. If drug was ineffective, it would never have re-entered the clinical trial and VRTX was running trials in Oxford for a while. I think safety is more of question than proof of concept. Preclinical models on this drug precursors like VX 821 and VX 822 are worth to read about. VRTX has huge patent protection portfolio for ART inhibitors. US government has patents for monoclonal antibodies for this target, so it is very valid drug target. Only AZN has a drug at present for this target.
Verity, thank you for pointing out that it may take more than 1 year for EU countries to reimburse for Orkambi use, and also that I did not include the likely participation by younger 508 homozygotes in the US. These two mistakes for the year 2016 roughly cancel each other, and in two years we may see substantial share price rise. Today's report that the New England Journal of Medicine published the results from Traffic and Transport studies is very encouraging.
I hope that Vertex has started some attempt to use CRISPR technology to put the missing phenylalanine base in the CFTR gene. It should be easier to convert heterozygous 508del into a homozygous 508del because existing DNA in the other allele can be used as template. Ultimately, exogenous CFTR DNA had to be delivered into the lung lining cells and other cells.
Sorry, you lost me. I think you're saying it doesn't work alone per the Chest article, which I agree with. What I was saying is that even if it does work alone per the FDAs theory, that won't mean it works alone enough for those who are heterozygotes for df508 because one df508 isn't enough protein on the cell surface...it is if there is already lots of it from another mutation 551D or some from another df508, but just one by itself and another mutation which doesn't make functioning protein wont cut it.
A few thoughts.
I think you overestimate the revenue this year and under next year. I think it will be 75% users by end of year but most coming on line in November and December. CFers only go in regularly every 3 months and I think the centers will do the scripting at normal appointments. And I think the preapproval process will drag things out more.
Unfortunately, I fear the EU is not going to reimburse on this or if it does not for a long time. :-((( My heart aches for those who won't have it.
On the other hand, I think you skipped entirely the 6-11 market. That is at minimum in U.S. 5500 and the results will be out in October and I expect FDA to quickly add the label to 6-11. I also expect uptake to be higher for 6-11 because the parents are the ones who have to "comply" and when its our kids....we just do it. Also, the parents of kids in that age group have been watching Vertex for the last 5-10 years ...the social media is just a different creature that I see a much faster uptick for that age range adding another 5000 users early in 2016. I also expect you'll get some more of 4-5 year olds getting off label, as they did with Kalydeco.
Finally, thank you for all the information and support you gave me in those early dark years when this was all Greek to me!!
VRTX announced today the NEJM, the most prestigious journal in clinical medicine, has published the results of the two PHASE 3 Orkambi clinical trials being considered by the FDA for approval of Orkambi, further validating the clinical significance of the data, as well as the concept of combining CFTR a potentiator, kalydeco, with correctors e.g. lumacaftor, 661, and next gen correctors to treat the underlying defect in the majority of CF patients.
First public presentation by the company following the Orkambi FDA ADCOM meeting, The fact VRTX CEO Leiden is the speaker may make this presentation more substantive than average, with the topics likely to detail both the CF pipeline and the plans for the market launch of Orkambi this summer, as well as the rest of the non CF pipeline. Hopefully the FDA will be announcing an early approval of Orakambi prior to July 5 PDUFA date, so that pricing and market launch will begin ahead of schedule and the 508dd CF population will finally have access to a drug that treats the underlying cause of their disease and prevents the ongoing destruction of their lungs.
cancer is a pretty crowded field, phase I trials don't excite investors, no matter how attractive the mode of action might be, all that counts is good phase II/phase III data, so it will take about two years before VX-803 and/or VX-970 will contribute to VRTX valuation.
Other trial results which could raise PE would be Phase I dose optimization study for VX-970 and VX-803. These molecules are inhibitors of ATR and possibly ATM as well. ATR and ATM are cell cycle checkpoint initiators. Tumor cells damaged by radiation, cisplatin, gemcitabine, or etoposide can be rescued by DNA repair, which cannot happen if the cell cycle is allowed to proceed. If DNA damaged cells enter the mitosis phase, irreparable chromosomal break would occur. VX-970 and VX-803 inhibit the checkpoint initiator so that damaged tumor cells are not stopped before the entry into mitosis phase where the tumor cells would be mortally wounded.
for a few bucks instead of spending $300,000 for the side effects. Nobody is going to buy or fund this #$%$ no matter who approves Orscambi.
VX-661 will achieve an absolute FEV1 change of 3 - 4%, and we have to give a minimum PE of at least 30. So you may expect 5.76 x 30 =$ 173/share by then. If the second generation correctors in the [oven] are really good in treating 508del heterozygotes, a PE of 75 is possible.
The net the company will be reimbursed for Orkambi pill would be assumed conservatively to be 200 K per year. The list price will be much higher, and cannot be much lower than the price of Kalydeco. If the price of Orkambi were much lower than that of Kalydeco, the 70% Kalydeco taking patients who have 508del mutation would switch to Orkambi because Orkambi can improve the FEV1 change by another 4% for people with 508del in one allele and Kalydeco responsive mutation in the other allele.
There are about 20,500 homozygous 508del persons (12 years old or older) in US and major EU markets. For this year, we can count on 8500 persons in the US. In the Lum+Iva rollover study, greater than 90% of Phase III participants joined the trial. Uptake of this combo will be slower than the speed of adoption by 551 CFers, and let us assume that an average of 75 % of 8500 homozygotes take the combo within 6 months of launch (by the end of the year). You get a revenue of 8500 x 0.75 x 200 K x 0.5 year = 638 Mln. Vertex projects to receive 570 Mln from Kalydeco responsive CFers. The annual company expenditure will not exceed 1.1 Bln (source: Vertex), and the tax for orphan drug sales is zero. Then, by the end of 2015 the net will be 108 Mln (= 638 Mln + 570 Mln - 1100 Mln). This corresponds to $ 0.39 per share.
For 2016, 200 Kalydeco taking CFer will be freed from the VX-661 Phase III trial to raise the sales to 600 Mln, the US sales from Orkambi will be 1.4 Bln, and the EU sales will be 800 Mln. Adding all three, we get 2.8 Bln. If R&D and SG&A amount to 1.2 Bln then, we have 1.6 Bln. Subtracting 10 % royalty payment to CF Foundation, we get 1.44 Bln. Dividing this figure with the number of shares which will be about 250 Mln, the earnings per share will be 1440 Mln/250 Mln = $ 5.76 per share.