Robin is the smartest of all analysts.
The only serious side effect coming from CD19-targeting CARs has to do with CRS (= cytokine release syndrome). But even this, it was found that an anti-interleukin-6 receptor antibody, with or without a steroid, has effectively and quickly reverse CRS, and has become a critical part of the CRS management. You can find this and other facts from a Journal of Clinical Oncology article called [Are all chimeric antigen receptors created equal?] written by JH Park and RJ Brentjens.
Sentiment: Strong Buy
I want to add to the excellent and conservative reply by Applejungle. For the next several years Vertex will not see any competition in treating underlying cause of CF unlike other biotech companies. Vertex CEO does not advertise drugs in preclinical development. Gilead's Harvoni sales will decrease by 60% or more when Regulus' RG-101 is launched in a few years. Celgene will face serious competition from several immunoncology drugs which are already marketed. For all drugs Isis develops against liver based proteins Alnylam can create far better ones...more effective and safer.
Specifically, Altshuler and his colleagues have shown that certain mutations in the SLC30A8 gene protects the carriers from contracting type 2 diabetes. This means that deletion of this gene would help people with T2D!!! However, other groups have shown that T2D is caused by mutation in the same gene in mice. This inconsistency can be resolved in favor of Altshuler if Vertex found an inhibitor to “loss of function” zinc transporter ZnT8 (encoded by SLC30A8) mutations. It is possible that Vertex has already found several compounds which exactly treat animal model T2D. This is a good reason for Altshuler to join the Vertex research group.
In real life, a mutation that abolishes the function of a protein useful in normal people, can reduce the risk of human disease in others. Examples include knockdown of antithrombin to treat hemophilia, or inhibition of PCSK9 function to treat hypercholesterolemia to potentially reduce heart attacks. But no target have yet been exhibited for type 2 diabetes (T2D) until this year. Would Vertex have potential drug candidates?
Dr. David Altshuler had been the second man in command at the prestigious Broad Institute in Cambridge, MA. Dr. Altshuler was also an associate professor of Genetics and Medicine at Harvard Medical School. His scientific research has focused on the discovery of causal connections between genetic mutation and health/disease. His most recent work involves genetic basis for the risk of developing type 2 diabetes (=T2D). Hence, he is an academic physician who is devoted for patient care. He is only 49 years young and a former classmate at Harvard Med tells me that he has a dynamic and friendly personality as well. He could have taken a position in any research or educational institution. Vertex is dedicated to bringing revolutionary medicine to the world, but it is not a pure research institution. I could not help but ask; what is he looking for at Vertex and what does Vertex expect to achieve by appointing an academic physician to occupy the position of CSO? As a geneticist Dr. Altshuler would be most gratified by finding out the genetic cause for a particular disease. Vertex as a biotech is interested in what molecule can cure the disease. Could these two separate goals converge?
Those two distinct goals can converge if medicine can be found based on genetic codes. What better way is there that can prove genetic basis of disease than inventing a molecule or a molecular process that can precisely repair the mutation? Altshuler’s hypothesis that certain genetic makeup is protected from T2D. This hypothesis is shown by genetic analysis of 150,000 human data, but other groups have shown earlier that the opposite is true. [read on]
[cont' from above]
A single subcutaneous dose of this anti-miR followed by a few weeks of any oral DAA will be good enough. And this will be preferred if the price for cure is lower. Furthermore, the best trial results for Genotype 3 with oral DAA combination is 90% or lower after 24 wks of dosing. Sovaldi + Riba combination cures only 65% of Genotype 3 patients. RG-101 can treat Genotype 3 patients as well as Genotype 1 or 2 because it knocks down the host molecule miR-122 which protects all Genotypes equally. There are a large number of Genotype 3 patients in EU and US. 20 - 50% of all HCV patients are infected with Genotype 3.
Direct-acting-antiviral (DAA) combos are remarkably effective in treating HCV patients. However, the dynamics of the marketing war among makers of DAAs will change in the future. Gilead, AbbVie, Merck, or J&J cannot ignore the potential of antimir-122 because a single dose of RG-101 at the lowest dose 2mg/kg can reduce the viral load by 4.1 log. This means that a single injection of 2mg/kg RG-101 destroys 99.99% of the viral genome present in patient blood 4 weeks later. Regulus is to report the clinical data for the single 4 mg/kg dosing in a month or so. The viral load reduction will be greater than 4 log at this dose. Regulus is also testing a single 8 mg/kg dosing.
Regulus also reported that at the 2mg/kg dose, 6 out of 14 patients had HCV RNA levels below the limit of quantification at day 29 and the 3 patients from this group who have reached day 57 still have HCV RNA levels below the limit of quantification. It is possible that some patients can achieve the SVR without any DAA, but when DAA combos are combined with RG-101, the remaining 0.01% of virus can be eliminate with a 99% SVR efficiency in a short duration of dosing.
All is possible because HCV RNA genome has an Achilles’ heel. DAAs don’t take advantage of this weakness of the virus. Sarnow, the godfather of miR-122 and HCV link, and colleagues published their latest results last August and found that miR-122, liver-specific miRNA, protects HCV from degradation by human RNAse called XRN2. When miR-122 is absent or reduced, XRN2 simply degrades the viral RNA. As far as I know, DAAs do not mess with miR-122. On the other hand, antimir-122 such as RG-101 can knockout miR-122 enough to cause XRN2 to destroy HCV genome profoundly without regard to the genotypes.
The treatment duration is important for compliance and cure. The shortest combo dosing for treatment available now is 8 weeks. [to continue]
Rojo, I learned after seeing your post that David Altshuler is a leader author of the 150 K man gene scanning NATURE GENETICS paper which identified the function of SCL30A8 and its relevance to type II diabetes. The strength of Vertex lies in finding structure-based inhibitors, or finding by screening a large number of small molecule inhibitors to a protein. Vertex could buy a CRISPR/Cas9 technology company to edit genes of SCL30A8 to disable its zinc transport function. Tell us more about your thinking.
Greed by the management of Gilead and high price of Sovaldi caused collapse for Gilead's stock price this morning. Fear mongers took advantage of that.
Right. Both Santaris and Regulus have been working on this miRNA-122 targeting drugs for several years. Santaris tested Telaprevir with Miravirsen. However, both development face a formidable challenge of all-oral drugs. Santaris has to come up with a drug better than 3 log reduction at 5 injections of 7 mg/kg dose. They better use the GalNAc delivery system of Alnylam as Regulus does. It will be difficult to compete against Harvoni if it takes 5 injections. Even 2 injections will be too many. The CEO of Regulus said the company may report the results from 2nd cohort, who takes a single 4 mg/kg dose, in January. I would not be surprised if the dose brings down viral load by 5 log.
A month ago, Regulus, a biotech specializing in drugs targeting micro-RNA, announced a surprising clinical results. Their second drug in development RG-101 knocked down HCV by 4.1 log with a single 1 ml subcu injection of a low 2mg/kg dose. Four weeks after this single dose, 6 out of 14 treatment naive and experienced patients treated with this low dose did not have any detectable virus in their blood. Several years ago Jopling and Sarnow showed that a human factor called mir-122 is essential for the survival of HCV genome in human body. Mir-122 is abundant only in hepatocytes and HCV can survive only in the liver for this reason. Very recently this year Sarnow showed that mir-122 forms a protective shield for HCV RNA against the host ribonuclease called XRN2. Without mir-122 HCV RNA will be degraded by the nuclease. Regulus is testing this drug with J&J's Simeprevir (OLYSIO) to study the effectiveness of the combination. The idea underlying the combination treatment is that 2 - 4 week OLYSIO regimen sandwiched between only two injections of RG-101 could destroy any genotype of HCV in patients.
So, Regulus has opened the potential to revolutionize hep C treatment. It has also opened the possibility that Vertex can once again market Telaprevir in combination with RG-101. The side effects plaguing Telaprevir+IFN+RIBA do not appear in the first 2-4 weeks of dosing in the majority of hep C patients and Telaprevir is as effective as Simeprevir. RG-101 is very very safe. Vertex management should consider testing Telaprevir in combination with RG-101. Simeprevir (OLYSIO) is absolutely useless by itself because of Gilead's Harvoni and Abbott's combo, and RG-101 may turn out to be its savior.
Economy sensitive areas are up in this early going. Biotech sector has been bearish since Friday.
Also, they are trying to increase the trading volume. They sweep up and down to catch trading interest. Buy below 110 if you can.
Kleanthis, the CEO, said in the Credit Suisse CC that the data from the second cohort (4mg/kg) will be ready in January. I predict that the a single shot of this 1 ml subcutaneous dose will reduce the viral load by 5 log in 4 wks on average. Many will achieve the SVR without oral combination.
Be careful how you trade.
I see a 4-way bidding war for the control of marketing RG-101.
AbbVie cannot afford to lose this anti-miR drug because their oral DAA combo is cumbersome to take for 12 weeks for treatment (two pills in the morning and one in the evening). By combining RG-101 with any one of their DAA (excl. Riba) would cut the treatment time to one third.
J & J has a protease inhibitor in Olysio which would be absolutely useless unless it is combined with RG-101. It is no wonder Regulus is tesing this combo.
Merck today announced that their trial to test a 4 wk regimen practically failed to see the market. Just adding RG-101 to any one of their drug can make a 4-wk regimen a possibility.
The company which would lose most from the success of RG-101 is Gilead. The sales of Harvoni will be cut by 50% or more. They may have to buyout for the survival of the company. They paid 11 B for Sovaldi. How much would they pay for RG-101?
A few years back I assumed a fast action such as the speed of ribonucleases to explain the rapid decrease of HCV counts immediately following the oral Hep C drug dosing in human patients. These drugs, such as incevek, sovaldi, and NS5A inhibitors, were designed to inhibit viral RNA replication, not to destroy existing HCV. The immunological destruction of HCV, I thought, would take much longer to observe the action. My assumption turned out to be right. Sarnow, the Father of mir-122 identification and HCV link, published a latest result to shed light on the connection between mir-122 and HCV survival. Oral DAAs also may act to interrupt mir-122 protection of HCV RNA from the nuclease attack. But, the direct action by anti-mir-122 on mir-122 eliminates the protection HCV RNA sought to find by binding to mir-122. With reduced mir-122 the exoribonuclease XRN2 simply degrades the viral RNA. I wonder a combination therapy is needed here. See below.
The abundant, liver-specific microRNA miR-122 forms extensive base-pairing interactions with the 5' noncoding region of the hepatitis C virus (HCV) RNA genome, protecting the viral RNA from degradation. We discovered that the 5'-3' exoribonuclease Xrn2, which plays a crucial role in the transcription termination of RNA polymerase II, modulates HCV RNA abundance in the cytoplasm, but is counteracted by miR-122-mediated protection. Specifically, Xrn2 depletion results in increased accumulation of viral RNA, while Xrn2 overexpression diminishes viral RNA abundance. Depletion of Xrn2 did not alter translation or replication rates of HCV RNA, but affected viral RNA stability. Importantly, during sequestration of miR-122, Xrn2 depletion restored HCV RNA abundance, arguing that Xrn2 depletion eliminates the miR-122 requirement for viral RNA stability. Thus, Xrn2 has a cytoplasmic, antiviral function against HCV that is counteracted by HCV's subversion of miR-122 to form a protective oligomeric complex at the 5' end of the viral genome.