Do you think that Nash FX small ph2 was done on purpose because they did not have enough funds to do a bigger trial and/or because by doing so they would attract more investment with further positive confirmation of drug efficacy in order to fund a bigger Nash FX pivotal trial and the Nash CX trial?
thanks. I was just trying to understand why, after doing a ph1 in Nash fibrosis, then they changed focus and started a (potentially pivotal) trial in Cirrhosis, without even doing a ph1... when you would have expected a ph2b in Nash Fibrosis, they started a small trial, which would definitively not be enough (given the size and the used enpoints, not validated I guess) for approval. It appears to me they somehow changed focus from Fibrosis to Cirrhosis. Was it an FDA recommendation? They did something similar with CNAT, when the FDA granted fast track in NASH LC.
It appears they are not using the Fibrotest, and in particular the Alpha-2 Macroglobulin component, anymore as in ph1, but replaced with LMS, but kept the Fibroscal for liver stiffness. Any thoughts on the Fibrotest replacement with LMS?
Also What is not clear to me, after the ph1 positive results in NASH fibrosis at highest dose why did they go directly with a NASH Cirrhosis ph2b, and not with a NASH Advanced Fibrosis ph2b (instead or as well)?
NASH FX :
•Difference between placebo and GR-MD-02 in the baseline adjusted mean change in liver fibrosis as measured by corrected T1 (cT1) mapping as determined from LiverMultiScan (LMS), a multi-parametric MRI protocol.
•Baseline-adjusted change in magnetic resonance elastography (as measured in kPa)
•Baseline-adjusted change in FibroScan Score (as measured in kPa)
In the ph1 results , NASH fibrosis for the 8mg/kg dose (same dosage used in ph2a), as it is also evident from the latest corporate presentation, fibrosis regression seem to increase with the number of doses. At 2nd dose the A2M reduction was ca 17%, after 3 days of the 4th dose (the last) the reduction was ca 20%, after 14 days from the 4th dose, there seemed to be a reuction in the regression vs baseline (going back to ca 15%).
To me it is clear that the administration of the GAL3 inhibitor should have continued to keep a further regression and that without it the risk of losing the benefit is very high.
Ph2a has double duration than ph1 , it spans over 16 weeks, with biweekly infusions, so we should see a further regression, after each infusion and the total regression at the end of the trial in the treated arm should hopefully be bigger than the maximum 20% experienced soon after the 4th infusion in ph1. Th same should apply to liver stiffness.
Because GAL3 is responsible for not only liver fibrosis but also for all other organ fibrosis. In developed world organ fibrosis accounts for 45% of ALL deaths. If GALT GAL3 inhibitor confirms effective in reducing fibrosis also in ph2 as in ph1 at 8mg/kg (same dose as used in ph2), then it will work also with other organs. How much is worth a drug which could save hundreds thousands , if not millions, of lives each year? I do not have $$ number quite frankly. That is why this is all so exciting, history can me made here!
Although probably it does not depend on them when the FDA is availaible for a meeting, I have a general feeling that management is not aggressive enough to get Emricasan to the market as quickly as possible, also considering that patents will expire in 2028. This view is also somehow based on the multiple small trials they are doing and their purpose which is not entirely clear IMO
I agree. As a matter of fact Emricasan has proved effective in reducing MELD score above 15 (minimum to enroll for transplant) and Portal pressure above 12 (clinical significant Portal Pressure) , whereas GAL3 inhibitor is bein tested in patients whose is at or below 15 and the primary endpoint is Portal Presssure. So they might complement each other, Emricasan for the very sick people and GAL 3 inhibitor for the moderately sick people. We shall see...
Do not feel embarassed for me. Calculation is easily done. 30% market share in just Nash Cirrhosis, means $9B revenue , applying avg pharma multiples, $40-$50B market cap. Yes it is embarassing how low the valuation of these two companies is. ICPT current market cap gives more the idea of where CNAT and/or GALT PPS should be now.BTW ICPT is not a competitor in Nash Cirrhosis and I do not think it will ever be
I think it has more to do with a non clear path forward approval. CNAT is doing multiple small trials and they have yet to agree with the FDA if they can do a ph2b or a ph3 in Nash LC. Also they have proved effective in high MELD score and High Portal Pressure subgroups, but Emricasan did not show stat sig reductions in the overall LC population.
GALT has more potential since GAL3 inhibition could work also in other organs fibrosis and in cancer. But GALT is behind as far as human testing is concerned (tested the current GAL3 inhibitor formulation in few people so far, while CNAT Emricasan has been tested in 450 people already and it has proved safe and effective in reducing severe Portal Pressure and MELD score above 15 in two ph2a) . If any or both of the two drugs is successful in LC and/or Fibrosis , I think sales could be in the billions of USD, successful GAL3 inhibitors could sell in the tens of USD if successful, but we are not sure so far if they work as well as (or better) in humans as with mice . Anyway both companies might trade at 1,000 + times current market cap, if successful.
Nash (advanced) fibrosis ph2a fully enrolled, results expected in September 2016.
Nash cirrhosis ph2b enrolling. Results expected end of 2017, potentially a pivotal trial (if results are good enough they could go for NDA directly based on what CEO said)
These are the only two companies (out of 3 , the third is GILD) developing a drug for Nash Cirrhosis. The market could be bigger than Nash Fibrosis as there are 900K patients in EU and US, but the chargeable price is much higher than to fibrosis patients. With at least $30K per annum per patient, we have a potential market of $27B just for US and EU. GALT and CNAT both capitalize less than $50M (with $20-30M in cash), and there is a good chance one of the two will be successful, their drug needs only to be good enough as there are no alternatives, and Cirrhosis can be fatal
That is the initial focus of both CNAT and GALT. The other company developing a Nash LC drug is GILD. Nash LC market in EU adn US is 900K patients, apply at least $30K per annum per patients and you get a potential market of $27B only for US and EU. It makes sense to be both in CNAT and GALT (both capitalizing less than $50M, with $20-$30M in cash), good chance one of the two will be successful, the successful drug could be good enough, not necessarily fantastic, as there is no alternative
Pulmonary hypertension is a highly lethal disease that transforms the thin, flexible vasculature of the lungs into thick, dysfunctional blood vessels that can kill.
Scientists believe that a protein highly expressed in the deadly disease is a major culprit as well as a potentially effective new treatment target.
They also have early evidence that a drug already in human studies for liver fibrosis can block or turn around early disease, said Dr. David Fulton, director of the Vascular Biology Center at the Medical College of Georgia at Augusta University.
Fulton and Dr. Scott Barman, pulmonary vascular biologist in the MCG Department of Pharmacology and Toxicology, are principal investigators on a $2.2 million National Institutes of Health grant that will enable them to better understand how the protein galectin-3, or gal-3, helps cause chronic, unhealthy remodeling of the lungs' blood vessels and maybe a way to stop it.
In humans as well as an animal model of the disease, the MCG scientists found increased gal-3 expression particularly in the media, the smooth muscle-rich middle layer of the artery that normally helps give blood vessels strength and flexibility. They've shown that, at least in culture, increasing levels of gal-3 increases unnatural proliferation and survival of these human smooth muscle cells, while silencing gal-3 decreases it.
"Excessive constriction makes the vessels small in the first place; inflammation and remodeling make it a permanent anatomical alteration," said Barman. Right heart failure is typically what kills patients, as that side of the heart is continually overtaxed trying to force blood inside the now-narrowed pulmonary arteries.
"The lung circulation is a high-capacity, low-resistance environment," said Fulton. "Any increase in resistance to blood flow is really damaging." There are a variety of causes. A small percentage of cases are idiopathic, or have no known cause, but known risk factors include heritable genetic mutations; heart disease, including congenital heart disease; emphysema; connective tissue problems such as lupus and scleroderma; obesity; drug side effects; and being female. Symptoms may include shortness of breath, dizziness, fatigue, a racing pulse, even chest pain and pressure. The blood vessels are too tiny and numerous to reopen once damaged. Rather, treatment includes vasodilators that may only extend life by a few years; a lung transplant is the final option. Stopping or somehow reversing the deadly chronic remodeling is the most important target now for scientists like Barman and Fulton.
Gal-3 is implicated as well in cancer, kidney fibrosis and liver fibrosis, diseases in which there also are excessive, unhealthy growth patterns, Barman said. A key goal of their new studies is not only blocking excessive gal-3 levels in pulmonary hypertension, but figuring out why the smooth muscle cells are committed to making the excessive levels. "Where is it coming from and where is it hitting?" Barman said.
They also want to identify epigenetic mechanisms, which underlie enduring changes in cell function that are thought to explain many of the wayward behaviors of cells in disease states."The smooth muscle cells proliferate, and they don't die," Fulton said.
As they put together the puzzle of how this disease happens, they also are looking at whether the gal-3 inhibitor they have been studying, GR-MD-02, continues to be effective at reversing or stopping the disease. Barman and Fulton are collaborating with Atlanta-based Galectin Therapeutics Inc. and its chief medical officer, Dr. Peter G. Traber, to look further at the gal-3 inhibitor the company developed and is now testing in humans with liver fibrosis.
While the inhibitor doesn't directly lower the gal-3 levels, it blocks its action, Fulton said. Ongoing studies will better determine optimal doses, and they have seen significant early disease reversal with the doses they have used, Barman said. Those findings were presented at the recent American Thoracic Society International Conference.
With treatment, smooth muscle cell growth normalizes, blood vessels relax and their opening, or lumen, widens. The new studies will include more severe models of disease that more closely reflect the stage at which many patients are diagnosed.
"The more we can reverse it later in disease, the more applicable the therapy becomes," Barman said, since by the time patients become symptomatic, the disease is fairly advanced. They also want to better identify the drug's points of action, which are unknown in the pulmonary circulation.
Growth and inflammation are necessary and important short-term in wound healing. "In normal wound healing, that goes away; in pulmonary hypertension, it just consolidates and gets worse," Fulton said, noting that under healthy circumstances, expression of gal-3 is low and its role largely unclear.
That is what he means. They could file for an Nda if data is strong enough
1) Results were strong enough for the FDA to grant approval
2) there is an immediate an urgent need of a safer medication
3) If they had a delay in the decision they would have announced it already (the FDA communicates it well in advance if they cannot make it for a certain deadline)
4) Since no delay, then they must have received the decision news yesterday
5) If it was bad news they would have released yesterday after hours whereas they want to have a maximum impact with a morning PR
One of the most intelligent post. Bump. If it was not illegal, it would be quite entertaining to watch how HF's have been manipulating LPCN price today and the past several months.