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The Odds are Up For The approval Of Incyte's (INCY) Melofibrosis Drug

Prohost Biotech - Tuesday, September 28, 2010

We will not lose our breath running after all the news posted about the biotech industry. We will restrict our selection to the most significant announcements. While there is good news about biotech firms’ breakthroughs, it is lost amid the mass of articles announcing or assessing the firms’ finances, routine events, meetings and plans (that may or may not come to pass), in addition to results from very early-phase trials that mean very little at their stage. The excessive amount of news has become confusing, especially that many are not mere news, but opinionated articles that contradict each other’s opinions with, or without relevance.

A case in point, Dendreon’s Provenge, the firm’s prostate cancer vaccine has just reached the market and yet, we are bombarded every day with articles, some highlighting the vaccine while others doubting its value. Each group has its backers of physicians, researchers and specialized analysts. It is obvious that what is meant to be read and believed is not about the vaccine’s efficacy or the lack of it, but about the stock price. Since the FDA approval of Provenge, DNDN has tremendously risen and risen again on good news about reimbursement then on news that a  prostate cancer drug developed by another firm has failed. The negative investors are finding it an opportunity to short the stock and advocate not buying it. Those who are positive on DNDN are advocating the opposite. One of these two opposing group will win in the short-term. We have no way to pinpoint the winning, or loosing group. The whole thing has come down to gambling, which is not our business.

Do these campaigns have anything to do with the vaccine’s efficacy? Common sense tells us that it is still early to tell. It all depends on the developing experience with the vaccine’s best use. It takes time to find thee most effective use of the vaccine or give up on it, which makes us be hopeful for the drug, but neutral on the firm’s stock at this stage.

Recently, trial results on breakthrough drugs have been announced. Some of the results are published in peer review journals, almost confirming the safety and efficacy of the drugs. Other results insinuate that approvals might be imminent even though the drugs did not solve all the major problems of the diseases they intend to treat. They demonstrated efficacy in alleviating detrimental symptoms, which deserves their presence on the market. The product we tackle today belongs to this second group. We will address both categories in upcoming articles. 

INCYTE’S (INCY) DRUG NBC 18424

NCB18424 is topping the news in the category of drugs that have chance of approval. The drug, which is partnered with Novartis is for the treatment of myeloproliferative diseases, which include myelofibrosis, polycythemia vera, and essential thrombocythemia. Recent promising results of phase 1/2 studies of NCB18424 on myelofibrosis were published in The New England Journal of Medicine. This rare, life-threatening hematologic disease is typified by malfunctioning fibrosed bone marrow that causes the formation of abnormally shaped red blood cells. The disease is characterized by bone marrow failure, anemia, enlarged spleen (splenomegaly), and debilitating symptoms, including extreme fatigue, poor quality of life, pancytopenia, weight loss and shortened survival, among other symptoms.

INCB18424 is a janus kinase (JAK) inhibitor. There are four Janus kinase families. JAK1 and JAK2 are involved in interferon-gamma signalling, whereas JAK1 and tyrosine kinase 2 (TYK2) are involved in type I interferon signaling. Mice that do not express TYK2 have defective natural cell killer function. Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon gamma, which is critical for innate and adoptive immunity against viral and intracellular bacterial infections and for tumor control. Aberrant interferon gamma expression is associated with a number of autoinflammatory and autoimmune diseases. The cytokine inhibits viral replication directly, and has immunostimulatory and immunomodulatory effects.  There is a strong association between abnormal JAK signaling and the development of myeloproliferative diseases.

Trial results of INCB18424 on myelofibrosis demonstrate that 70% to 82% of patients receiving oral INCB18424 twice daily had marked reduction i(25% or more) in palpable spleen size that was durable for more than a year of follow-up. More than half the subjects treated with an optimized dose regimen, which began with 15 mg twice daily, achieved at least a 50% reduction in palpable spleen size. This marked reduction was confirmed using objective measurements by MRI, where 48% of patients on optimized regimens had at least a 35% reduction in spleen volume. After one month of therapy, patients with symptoms including fatigue, night sweats and pruritus achieved more than 50% improvement in symptom scores.

Patients with prior weight loss, experienced a clinically meaningful gain in total body weight following treatment. The drug caused improvement in patients’ performance status, increased exercise capacity, reductions of circulating cytokines (inflammation-causing proteins in the blood, which are markedly elevated in patients with myelofibrosis.

Two Phase 3 clinical trials, COMFORT-I in the US, Canada and Australia, and COMFORT-II in Europe, have completed enrollment and are evaluating the benefits of treatment with INCB18424 compared to either placebo or best available treatment.

Conclusion: The discovery of JAK mutations common to myelofibrosis, polycythemia vera and essential thrombocythemia, has linked them on a molecular level. Together with the fact that the patients tend to have elevated inflammatory cytokines that signal through JAK1 and JAK2, led Incyte to the discovery and development of INCB18424, a potent, selective inhibitor of the JAK1 and JAK2 tyrosine kinases. So, there exist a solid rationale behind the development of the drug for the selected diseases. Results of trials also support the scientific promise of JAK1 and JAK2 inhibition in the treatment of myeloproliferative neoplasms as demonstrated in the clinical improvement that might have been achieved for the first time in treating myelofibrosis, as Paul A. Friedman, Chief Executive Officer and President of Incyte has stated.

For the victims of myelofibrosis and their doctors, they have yet to see whether the clinical improvements experienced would contribute to increased survivability, especially that the drug seems to have been unsuccessful in reversing the anemia, despite its success in shrinking the spleen size. Maybe red blood growth factor, or any other product added to INCB18424 would do the job remains to be seen. On the other hand, shrinking the enlarged spleen is, by itself, a great achievement. A tremendous increase in spleen size poses a huge discomfort and great negative impact on patients’ wellbeing. Adding the other clinical improvements to the effect of the drug on the spleen would motivate the FDA to approve the drug.

For investors, myelofibrosis has a minute market, but the drug promises to treat many diseases. Also, the firm’s technology and product pipeline are promising. Results of the drug on polycythemia vera are encouraging, which add to the market’s size in case of approval. We will be following up on this firm’s activities, focusing on its products’ early and late clinical trials. Added to the drug intended for myeloproliferative diseases, the addition of the firm’s molecules addressing inflammatory diseases could turn this small firm into a full-fledged drug developer. 

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