On 5.26.10 I forwarded the following comment to Food and Drug Administration:
The decision of the Food and Drug Administration (FDA) not to approve pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) was highly disappointing to all patinets suffering from this disease, their caregivers, as well as physicians who are treating IPF patients. The fact that that the Agency did not follow the advice of their Advisory Committee, which voted 9:3 for the approval of pirfenidone, is extremely disturbing. The Agency also did not listen to pleas of patients who have been waiting impatiently for any drug that could possibly offer some hope in alleviating their suffering or prolonging their life expectancy. The Agency found it impossible to deviate from the established guidelines, even though the safety of pirfenidone was not quetioned.
The request for another Phase III trial to confirm the efficacy of pirfenidone may sound reasonable, but in reality it makes the eventual marketing of pirfenidone unlikely, even if another trial confirms its efficacy. Al leaast 4 years and a few hundred millions of dollars will be needed for another trial and its evaluation. If the trial starts in 2011, FDA approval cannot be expected before 2015. The proposed use of pirfenidone in IPF is covered, however by a 1997 patent that will expire in 2014. No single pharmaceutical company can afford to pay for the development and marketing of a drug without patent protection and/or a few years of exclusivity.
No drug can be expected to produce absolutely conclusive results in patients with IPF. IPF is most probably not a single disease but a collection of fibrotic lung diseases with unknown causes, so that in respect to etiology the patient population will be heterogenous and pirfenidone cannot, therefore, be expected to help all IPF patients. The fact that pirfenidone helps some of the patients with IPF should provide an adequate basis for its approval, since the risk-benefit ratio favors the drug.
A possible solution for the FDA is to create a new category of drugs with only "conditional approval" which would not cary an approved disease indication, but would claim, like for "dietary supplements", only a possible supporting role in the maintenance of function of certain organs (lungs in the case of pirfenidone). These drugs could be conditionally appproved by FDA on the basis of their safety record and the medical profession could be responsible for their use in specific diseases. This "conditional approval" could be withdrawn after 5 years, if additional documentation is not provided. After completion of all required clinical trials a final approval would be considered. In any case, I hope that the FDA would be willing to reconsider or to modify their decision to request another Phase III trial for pirfenidone.
Sincerely, Alexander Scriabine, M.D., Guilford, CT, May 26. 2010
Pharmacologist and IPF patient
Wednesday, May 26, 2010
Wednesday, February 10, 2010
FDA meeting on pirfenidone
FDA Advisory Committee is meeeting on March 9 2010 to consider approval of pirfenidone for the treatment of pulmonary fibrosis. I am submitting the following opinion to FDA to be considered at this meeting:
My Experience with Idiopathic Pulmonary Fibrosis (IPF)
I am a retired MD pharmacologist and for the last 9 years an IPF patient.
As a patient I experienced an unusually slow progression of the disease: a gradual suffocation leading to a loss of my ability to run, climb stairs and now even walk without oxygen. Attacks of a severe unproductive cough have made the life particularly miserable. I am a patient at Yale pulmonary clinic but the best pulmonary physicians cannot cure me. I am not eligible for lung transplantation and my therapy consists only of oxygen, since there are no drugs capable of alleviating my suffering. In the clinic I am having annual pulmonary function tests to document a gradual decline in most parameters. There is also a support group of patients with IPF to share experiences. I am learning that some of the patients are in worse shape than I am. They are in wheelchairs and can no longer dress or take a shower without the help of a caregiver. I can see myself in a similar situation in the near future.
As a scientist I am deeply disturbed by our failure to recognize the medical need and to develop drugs for the treatment of IPF. Very little research is ongoing in this field at either academic institutions or the pharmaceutical industry. I spent a good portion of the last year researching IPF and the approaches to its therapy. My research culminated in an extensive review article published last December (Scriabine A and Rabin D.U.. New developments in the therapy of pulmonary fibrosis. In: Contemporary aspects of biomedical research: drug discovery. Enna S.J. and Williams, M. Eds. Academic Press 2009; 419-464). Targets for antifibrotic drugs have been proposed and models of fibrotic diseases are available, but only pirfenidone offers some hope for IPF patients in the near future. IPF is probably not a single disease, but a group of pulmonary diseases with similar pathology, but different etiology. If so, one drug is not likely to help every patient diagnosed with IPF and clinical trials will not demonstrate uniform efficacy in a heterogeneous population. Under these circumstances safety should be the major consideration for drug approval.
Alexander Scriabine, MD
ascriabine@comcast.net
435 Colonial Road
Guilford, CT 06437
FDA Advisory Committee is meeeting on March 9 2010 to consider approval of pirfenidone for the treatment of pulmonary fibrosis. I am submitting the following opinion to FDA to be considered at this meeting:
My Experience with Idiopathic Pulmonary Fibrosis (IPF)
I am a retired MD pharmacologist and for the last 9 years an IPF patient.
As a patient I experienced an unusually slow progression of the disease: a gradual suffocation leading to a loss of my ability to run, climb stairs and now even walk without oxygen. Attacks of a severe unproductive cough have made the life particularly miserable. I am a patient at Yale pulmonary clinic but the best pulmonary physicians cannot cure me. I am not eligible for lung transplantation and my therapy consists only of oxygen, since there are no drugs capable of alleviating my suffering. In the clinic I am having annual pulmonary function tests to document a gradual decline in most parameters. There is also a support group of patients with IPF to share experiences. I am learning that some of the patients are in worse shape than I am. They are in wheelchairs and can no longer dress or take a shower without the help of a caregiver. I can see myself in a similar situation in the near future.
As a scientist I am deeply disturbed by our failure to recognize the medical need and to develop drugs for the treatment of IPF. Very little research is ongoing in this field at either academic institutions or the pharmaceutical industry. I spent a good portion of the last year researching IPF and the approaches to its therapy. My research culminated in an extensive review article published last December (Scriabine A and Rabin D.U.. New developments in the therapy of pulmonary fibrosis. In: Contemporary aspects of biomedical research: drug discovery. Enna S.J. and Williams, M. Eds. Academic Press 2009; 419-464). Targets for antifibrotic drugs have been proposed and models of fibrotic diseases are available, but only pirfenidone offers some hope for IPF patients in the near future. IPF is probably not a single disease, but a group of pulmonary diseases with similar pathology, but different etiology. If so, one drug is not likely to help every patient diagnosed with IPF and clinical trials will not demonstrate uniform efficacy in a heterogeneous population. Under these circumstances safety should be the major consideration for drug approval.
Alexander Scriabine, MD
ascriabine@comcast.net
435 Colonial Road
Guilford, CT 06437
Friday, January 15, 2010
Pulmonary Alveolar Proteinosis (PAP) vs Idiopathic Pulmonary Fibrosis (IPF) - Diagnostic Considerations
PAP is a rare clinical syndrome that is characterized by the accumulation of surfactant in the pulmonary airspaces (Greenhill SR and Kotton DN, 2009). Lung biopsies usually reveal presence of diastase-resistant intra-alveolar exudate with minimal interstitial fibrosis and "honeycombing". In some patients with PAP, however, interstitial fibrosis can be considerable and at least two PAP patients were initially thought to have IPF (Arbiser ZK et al., 2003). PAP is no longer idiopathic, since functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to cause the disease. The presence of autoantibodies against GM-CSF in serum is considered to be diagnostic for PAP (Kitamura T et al., 1999; Bonfield, TL et al., 2002). It is highly important to excude PAP as a possible diagnosis since the prognosis of PAP and IPF are different. The life expectancy of PAP patients is longer, 5-year mortality is 20% vs 80% for IPF patients. Also, patients with PAP favorably respond to pulmonary lavage and can possibly be treated with GM-CSF. It is unfortunate that GM-CSF antibodies test is not yet widely available in clinical laboratories.
Arbiser ZK et al. Ann Diagn Pathol 7:82-86, 2003
Bonfield TL et al. Clin Immunol 105:324-350, 2002.
Greenhill SR and Kotton. Chest 136:571-577, 2009
Kitamura T et al. J Exp Med 190:875-880, 1999.
PAP is a rare clinical syndrome that is characterized by the accumulation of surfactant in the pulmonary airspaces (Greenhill SR and Kotton DN, 2009). Lung biopsies usually reveal presence of diastase-resistant intra-alveolar exudate with minimal interstitial fibrosis and "honeycombing". In some patients with PAP, however, interstitial fibrosis can be considerable and at least two PAP patients were initially thought to have IPF (Arbiser ZK et al., 2003). PAP is no longer idiopathic, since functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to cause the disease. The presence of autoantibodies against GM-CSF in serum is considered to be diagnostic for PAP (Kitamura T et al., 1999; Bonfield, TL et al., 2002). It is highly important to excude PAP as a possible diagnosis since the prognosis of PAP and IPF are different. The life expectancy of PAP patients is longer, 5-year mortality is 20% vs 80% for IPF patients. Also, patients with PAP favorably respond to pulmonary lavage and can possibly be treated with GM-CSF. It is unfortunate that GM-CSF antibodies test is not yet widely available in clinical laboratories.
Arbiser ZK et al. Ann Diagn Pathol 7:82-86, 2003
Bonfield TL et al. Clin Immunol 105:324-350, 2002.
Greenhill SR and Kotton. Chest 136:571-577, 2009
Kitamura T et al. J Exp Med 190:875-880, 1999.
Monday, January 4, 2010
IPF symptomatology
The first symptom of my disease, idiopathic pulmonary fibrosis (IPF), was cough. It appeared to be caused by a post-nasal drip. I assumed that my sinuses may have been infected and I contacted otolaryngologist who ordered scan of the sinuses and found nothing. The cough was initially non-productive, it lasted for ca 30 minutes every morning and subsided after breakfast. IPF was diagnosed at Yale pulmonary clinic on the basis of X-ray, pulmonary function tests and lung scan. It was explained to me that IPF is a terminal disease and that there are no FDA approved drugs for the treatment of IPF. The only therapy, recommended by the Thoracic society, consists of steroids (e.g. prednisolone) and/or immunosuppressants (e.g. azathioprine). This therapy has not been shown to prolong life expectancy, is ineffective in the majority of patients and is associated with substantial side effects. I chose not to be treated and used candies to reduce the severity of cough. I learned from the literature that antioxidants may have antifibrotic activity and treated myself with vitamin C (slow release), 1 g per day and N-acetyl cysteine ( 2 x 600 mg per day). The only other symptom I experienced early in the disease was what I called, "miniapnea", inability to breathe for a few seconds, followed by complete recovery. Thereafter, dyspnea during and after exertion became the major symptom.
Initially it was uphill walking that caused dyspnea, but gradually walking on the flat surface became difficult as well. Dyspnea was associated with oxygen desaturation, as measured with oximeter. Climbing steps to the 2nd floor at home reduced blood oxygen saturation very rapidly from 95% to 85 and eventually even to 78%. Breathing oxygen at 2 L/min for 5 to 10 minutes normalized oxygen levels. Desaturation below 90% was associated with dyspnea, dizziness, anxiety and occasional chest pain. The symptoms were proportional to the decrease in blood oxygen, they rapidly disappeared after oxygen inhalation. Thermoregulation appeared to be affected as well. Exposure of the skin to cold temperature led to oxygen desaturation and cough.
Another symptom was "burning feet" at night that was independent of actual skin or room temperature. The sensation was the same when the feet were hot or cold. Still another symptom was "running nose", nasal discharge of a very thin fluid, that was more pronounced during and after administration of oxygen.
Domestic tasks became difficult, I routinely desaturated in shower and switched to bath every second day. Initially, I could exercise on treadmill while inhaling oxygen, but later oxygen inhalation even at 3 L/min did not protect from desaturation during exercise. The disease appeared to progress in steps. The steps were initiated by common cold or other stress. Annual lung function tests indicated gradual decrease in vital capacity. I found it more and more difficult to maintain blood oxygen levels above 90%. According to the literature only 20% of patients are expecxted to survive 5 years after diagnosis. I am already in my 8th year. Does this mean that diagnosis may have been incorrect?
Initially it was uphill walking that caused dyspnea, but gradually walking on the flat surface became difficult as well. Dyspnea was associated with oxygen desaturation, as measured with oximeter. Climbing steps to the 2nd floor at home reduced blood oxygen saturation very rapidly from 95% to 85 and eventually even to 78%. Breathing oxygen at 2 L/min for 5 to 10 minutes normalized oxygen levels. Desaturation below 90% was associated with dyspnea, dizziness, anxiety and occasional chest pain. The symptoms were proportional to the decrease in blood oxygen, they rapidly disappeared after oxygen inhalation. Thermoregulation appeared to be affected as well. Exposure of the skin to cold temperature led to oxygen desaturation and cough.
Another symptom was "burning feet" at night that was independent of actual skin or room temperature. The sensation was the same when the feet were hot or cold. Still another symptom was "running nose", nasal discharge of a very thin fluid, that was more pronounced during and after administration of oxygen.
Domestic tasks became difficult, I routinely desaturated in shower and switched to bath every second day. Initially, I could exercise on treadmill while inhaling oxygen, but later oxygen inhalation even at 3 L/min did not protect from desaturation during exercise. The disease appeared to progress in steps. The steps were initiated by common cold or other stress. Annual lung function tests indicated gradual decrease in vital capacity. I found it more and more difficult to maintain blood oxygen levels above 90%. According to the literature only 20% of patients are expecxted to survive 5 years after diagnosis. I am already in my 8th year. Does this mean that diagnosis may have been incorrect?
Tuesday, October 6, 2009
October 6, 2009
Antioxidants in the treatment of IPF (idiopathic pulmonary fibrosis)
The disturbance of pulmonary antioxidant/oxidant balance leading to oxidative stress is thought to be one of the major factors contributing to the development of IPF ( Kinnula and Myllärniemi, 2008; Walters et al., 2008). In patients with IPF there is an excessive production of so-called reactive oxygen species (ROS): superoxide anion (O2-), hydrogen peroxide (H2O2), peroxynitrite and hydroxyl radicals (OH-). ROS damage proteins, lipids and other cellular macromolecules, activate profibrotic cytokines, and consequently enhance fibrosis. Production of ROS is increased in animals with bleomycin-induced fibrosis and ROS are required for the development of bleomycin-induced fibrosis in mice (Manoury et al., 2005). In animals fibrosis can be prevented or reduced by antioxidants (Kilinç et al, 1993). Taken together these data support the notion that antioxidant therapy may have a beneficial effect in the treatment of IPF.
Many antioxidants occur naturally in the body and/or are regularly present in the human diet. Glutathione, vitamins E and C, polyphenols and uric acid belong to this group. Numerous antioxidant polyphenols are present in plants, vegetables and fruits. Indeed, curcumin (Biswas et al., 2005) and resveratrol (Sener et al., 2007) ameliorate bleomycin-induced pulmonary fibrosis in rats. Glutathione is a major antioxidant in lungs. In addition to its antioxidant activity, glutathione suppresses the proliferation of human lung fibroblasts (Cantin et al., 1990) and regulates the fibrogenic effects of transforming growth factor beta (TGFβ) (Ono et al., 2009). Since glutathione does nor readily penetrate the cell membrane, and has bronchoconstrictor activity, most experimental studies were performed with its thiol precursor, N-acetyl cysteine (NAC). Other thiols or prodrugs known to be metabolized to thiols, such as erdosteine, have also been shown to prevent bleomycin-induced fibrosis in laboratory animals (Day, 2008). Animal studies strongly suggest that NAC and other antioxidants should be useful in the therapy of patients with IPF.
Biswas, S.K., McClure, D., Jimenez, L.A., Megson, I.L, and Rahman, I. (2005). Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxid. Redox. Signal. 7:32-41.
Cantin, A.M., North, S.L., Felis, G.A., Hubbard, R.C., and Crystal, R.G. (1987). Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J. Clin. Invest. 79:1665-1673.
Day, B.J. (2008). Antioxidants as potential therapeutics for lung fibrosis. Antioxid. Redox Signal. 10:355-371 .
Kilinç, C. Ozean, O,. Karaoz, E., Sunguroglu, K., Kuluay, T., an Karaca, L. (1993). Viamin E reduces bleomycin-induced fibrosis in mice: biochemical and morphological studies. J. Basic. Clin. Physiol. Pharmacol. 4: 249-269.
Kinnula V.L. and Myllärniemi, M. (2008). Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid. Redox. Signal. 10: 727- 738.
Manouri, B., Nenan, S., Leclerc, O., Guenon, I., Boichot, E., Planquois, J-M., Bertrand, C.P., and Lagente, V. (2005). The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res. 6:11-23.
Ono, A, Utsugi, M., Masubuchi, K., Ishizuka, T., Kawata, T., Shimizu, Y., Hisada, T., Hamuro, J., Mori, M., Dobashi, K. (2009). Glutathione redox regulates TGFβ –induced fibrogenic effects through Smad3 activation. FEBS Lett 583: 357-362.
Sener, G., Topaloglu, N., Sehirtli, A.O., Ercan, F. and Gedik, N. (2007). Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm. Pharmacol. Ther. 20:642-649.
Walters, D.M., Cho, H-Y and Kleeberger, S.R. (2008). Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid. Redox Signal. 10:321-332.
Antioxidants in the treatment of IPF (idiopathic pulmonary fibrosis)
The disturbance of pulmonary antioxidant/oxidant balance leading to oxidative stress is thought to be one of the major factors contributing to the development of IPF ( Kinnula and Myllärniemi, 2008; Walters et al., 2008). In patients with IPF there is an excessive production of so-called reactive oxygen species (ROS): superoxide anion (O2-), hydrogen peroxide (H2O2), peroxynitrite and hydroxyl radicals (OH-). ROS damage proteins, lipids and other cellular macromolecules, activate profibrotic cytokines, and consequently enhance fibrosis. Production of ROS is increased in animals with bleomycin-induced fibrosis and ROS are required for the development of bleomycin-induced fibrosis in mice (Manoury et al., 2005). In animals fibrosis can be prevented or reduced by antioxidants (Kilinç et al, 1993). Taken together these data support the notion that antioxidant therapy may have a beneficial effect in the treatment of IPF.
Many antioxidants occur naturally in the body and/or are regularly present in the human diet. Glutathione, vitamins E and C, polyphenols and uric acid belong to this group. Numerous antioxidant polyphenols are present in plants, vegetables and fruits. Indeed, curcumin (Biswas et al., 2005) and resveratrol (Sener et al., 2007) ameliorate bleomycin-induced pulmonary fibrosis in rats. Glutathione is a major antioxidant in lungs. In addition to its antioxidant activity, glutathione suppresses the proliferation of human lung fibroblasts (Cantin et al., 1990) and regulates the fibrogenic effects of transforming growth factor beta (TGFβ) (Ono et al., 2009). Since glutathione does nor readily penetrate the cell membrane, and has bronchoconstrictor activity, most experimental studies were performed with its thiol precursor, N-acetyl cysteine (NAC). Other thiols or prodrugs known to be metabolized to thiols, such as erdosteine, have also been shown to prevent bleomycin-induced fibrosis in laboratory animals (Day, 2008). Animal studies strongly suggest that NAC and other antioxidants should be useful in the therapy of patients with IPF.
Biswas, S.K., McClure, D., Jimenez, L.A., Megson, I.L, and Rahman, I. (2005). Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxid. Redox. Signal. 7:32-41.
Cantin, A.M., North, S.L., Felis, G.A., Hubbard, R.C., and Crystal, R.G. (1987). Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J. Clin. Invest. 79:1665-1673.
Day, B.J. (2008). Antioxidants as potential therapeutics for lung fibrosis. Antioxid. Redox Signal. 10:355-371 .
Kilinç, C. Ozean, O,. Karaoz, E., Sunguroglu, K., Kuluay, T., an Karaca, L. (1993). Viamin E reduces bleomycin-induced fibrosis in mice: biochemical and morphological studies. J. Basic. Clin. Physiol. Pharmacol. 4: 249-269.
Kinnula V.L. and Myllärniemi, M. (2008). Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid. Redox. Signal. 10: 727- 738.
Manouri, B., Nenan, S., Leclerc, O., Guenon, I., Boichot, E., Planquois, J-M., Bertrand, C.P., and Lagente, V. (2005). The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res. 6:11-23.
Ono, A, Utsugi, M., Masubuchi, K., Ishizuka, T., Kawata, T., Shimizu, Y., Hisada, T., Hamuro, J., Mori, M., Dobashi, K. (2009). Glutathione redox regulates TGFβ –induced fibrogenic effects through Smad3 activation. FEBS Lett 583: 357-362.
Sener, G., Topaloglu, N., Sehirtli, A.O., Ercan, F. and Gedik, N. (2007). Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm. Pharmacol. Ther. 20:642-649.
Walters, D.M., Cho, H-Y and Kleeberger, S.R. (2008). Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid. Redox Signal. 10:321-332.
Monday, September 28, 2009
Animal Models of Pulmonary Fibrosis
Reliable animal disease models greatly facilitate drug development, even when the precise trigger of a disease is unknown. Since this is the case with idiopathic pulmonary fibrosis (IPF), the availability of an animal model is particularly important for successful development of antifibrotic drugs. The standard models of pulmonary fibrosis are bleomycin-treated rodents. Extensive reviews of the bleomycin model and of its use in pulmonary research were recently published (Moeller et al., 2008). A single intratracheal administration of bleomycin produces pulmonary fibrosis in rodents, with a maximal effect at between 20 to 28 days after exposure to the drug. Thereafter fibrosis slowly resolves. The cause and the spontaneous resolution of fibrosis differentiate this model from IPF in humans, although it is similar with respect to the production of cytokines and free radicals. Moeller et al. listed published studies on the prevention or treatment of bleomycin-induced fibrosis in laboratory animals. They point out that to mimic clinical situations the potential antifibrotic drugs should be administered after, and not prior to, the development of bleomycin-induced fibrosis. Antioxidants, angiotensin converting enzyme inhibitors, angiotensin antagonists, immunosuppressants, macrolide antibiotics and many other agents are reported to reduce fibrosis in bleomycin-treated animals. Most of the drugs were never tested for antifibrotic activity in humans whereas others were ineffective in clinical trials. However, the fact that pirfenidone is effective in this model, and has yielded promising clinical results in a Phase III trial, suggests the potential utility of this model in drug discovery.
Other drugs or chemicals known to produce pulmonary fibrosis in humans are also
used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Leeder et al. (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC). Pulmonary fibrosis can be also produced in rats by paraquat and the angiotensin converting enzyme inhibitors captopril and enalapril reduce paraquat-induced pulmonary fibrosis in rats (Ghazi-Khansari et al., 2007). Parra et al. (2008) induced pulmonary fibrosis in mice by butyl-hydroxytoluene and found it to be histologically identical to fibrosis in humans with IPF. Ask et al. (2008) have induced pulmonary fibrosis in rats by adenoviral gene transfer of transforming growth factor beta (TGFβ) and assessed progression of the disease by non-invasive techniques.
Attempts have also been made to develop in vitro models of pulmonary fibrosis. As an example, cadmium chloride in combination with TGFβ produces fibrosis in rat lung slice cultures (Lin et al., 1998).
The adequate technology for the preclinical evaluation of potential antifibrotic drugs is available, although it is obvious that neither animal models nor in vitro techniques mimic the human condition in all respects.
Ask, K., Labiris, R., Farkas, L., Moeller, A., Froese, A., Farncombe, T., McClelland, G.B., Inman, M., Gauldie, J., and Martin, R.J. (2008). Comparison between conventional and “clinical” assessment of lung fibrosis. J Transl Med 6:16.
Cantor, J.O., Osman, M., Cerreta, J.M., Suarez, R., Mandi, I., and Turino, G.M. (1984). Amiodarone-induced pulmonary fibrosis in hamsters. Exp. Lung. Res. 6:1-10.
Ghazi-Khansari, M., Mohammadi-Karakani, A., Sotoudeh, M., Mokhtary, P., Pour-Esmaeil, E., Maghsoud, S. (2007). Antifibrotic effect of captopril and enalapril on paraquat-induced fibrosis in rats. J. Appl. Toxicol. 27:342-349.
Leeder, R.G., Brien, J.F., and Massey T.E. (1994). Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. Can. J. Physiol. Pharmacol. 72:613-621.
Lin, C.J., Yang, P.C., Hsu, M.T., Yew, F.H., Liu, T.Y., Shun, C., Tyan, S.W., and Lee, T.C. (1998). Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming factor –beta1. Toxicology 127: 157-166.
Moeller, A., Ask, K., Warburton, D., Gauldie, J., and Kolb, M. (2008). The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40:362-382.
Parra, E.R., Boufelli, G., Berthanha, F., Samorano, Lde.P., Aguiar, A.C. Jr., Costa, F.M., Capelozzi, V.L., Barbas-Filho, J.V. (2008). Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene. Int. J. Exp. Pathol. 89:350-357.
Alex Scriabine, MD
Guilford, CT
Reliable animal disease models greatly facilitate drug development, even when the precise trigger of a disease is unknown. Since this is the case with idiopathic pulmonary fibrosis (IPF), the availability of an animal model is particularly important for successful development of antifibrotic drugs. The standard models of pulmonary fibrosis are bleomycin-treated rodents. Extensive reviews of the bleomycin model and of its use in pulmonary research were recently published (Moeller et al., 2008). A single intratracheal administration of bleomycin produces pulmonary fibrosis in rodents, with a maximal effect at between 20 to 28 days after exposure to the drug. Thereafter fibrosis slowly resolves. The cause and the spontaneous resolution of fibrosis differentiate this model from IPF in humans, although it is similar with respect to the production of cytokines and free radicals. Moeller et al. listed published studies on the prevention or treatment of bleomycin-induced fibrosis in laboratory animals. They point out that to mimic clinical situations the potential antifibrotic drugs should be administered after, and not prior to, the development of bleomycin-induced fibrosis. Antioxidants, angiotensin converting enzyme inhibitors, angiotensin antagonists, immunosuppressants, macrolide antibiotics and many other agents are reported to reduce fibrosis in bleomycin-treated animals. Most of the drugs were never tested for antifibrotic activity in humans whereas others were ineffective in clinical trials. However, the fact that pirfenidone is effective in this model, and has yielded promising clinical results in a Phase III trial, suggests the potential utility of this model in drug discovery.
Other drugs or chemicals known to produce pulmonary fibrosis in humans are also
used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Leeder et al. (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC). Pulmonary fibrosis can be also produced in rats by paraquat and the angiotensin converting enzyme inhibitors captopril and enalapril reduce paraquat-induced pulmonary fibrosis in rats (Ghazi-Khansari et al., 2007). Parra et al. (2008) induced pulmonary fibrosis in mice by butyl-hydroxytoluene and found it to be histologically identical to fibrosis in humans with IPF. Ask et al. (2008) have induced pulmonary fibrosis in rats by adenoviral gene transfer of transforming growth factor beta (TGFβ) and assessed progression of the disease by non-invasive techniques.
Attempts have also been made to develop in vitro models of pulmonary fibrosis. As an example, cadmium chloride in combination with TGFβ produces fibrosis in rat lung slice cultures (Lin et al., 1998).
The adequate technology for the preclinical evaluation of potential antifibrotic drugs is available, although it is obvious that neither animal models nor in vitro techniques mimic the human condition in all respects.
Ask, K., Labiris, R., Farkas, L., Moeller, A., Froese, A., Farncombe, T., McClelland, G.B., Inman, M., Gauldie, J., and Martin, R.J. (2008). Comparison between conventional and “clinical” assessment of lung fibrosis. J Transl Med 6:16.
Cantor, J.O., Osman, M., Cerreta, J.M., Suarez, R., Mandi, I., and Turino, G.M. (1984). Amiodarone-induced pulmonary fibrosis in hamsters. Exp. Lung. Res. 6:1-10.
Ghazi-Khansari, M., Mohammadi-Karakani, A., Sotoudeh, M., Mokhtary, P., Pour-Esmaeil, E., Maghsoud, S. (2007). Antifibrotic effect of captopril and enalapril on paraquat-induced fibrosis in rats. J. Appl. Toxicol. 27:342-349.
Leeder, R.G., Brien, J.F., and Massey T.E. (1994). Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. Can. J. Physiol. Pharmacol. 72:613-621.
Lin, C.J., Yang, P.C., Hsu, M.T., Yew, F.H., Liu, T.Y., Shun, C., Tyan, S.W., and Lee, T.C. (1998). Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming factor –beta1. Toxicology 127: 157-166.
Moeller, A., Ask, K., Warburton, D., Gauldie, J., and Kolb, M. (2008). The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40:362-382.
Parra, E.R., Boufelli, G., Berthanha, F., Samorano, Lde.P., Aguiar, A.C. Jr., Costa, F.M., Capelozzi, V.L., Barbas-Filho, J.V. (2008). Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene. Int. J. Exp. Pathol. 89:350-357.
Alex Scriabine, MD
Guilford, CT
Monday, September 21, 2009
WHERE ARE DRUGS FOR TREATMENT OF IPF (IDIOPATHIC PULMONARY FIBROSIS)?_
During the last decade extensive research has been conducted on IPF and therapeutic approaches to treat this condition. New targets for drug development, as well as new leads, were identified. However, there are still no FDA-approved drugs for the treatment of this condition
There have been several barriers to the development of effective therapeutics for IPF. One is the fact that IPF is considered an orphan disease because of its prevalence, lessening the urgency for finding a cure. Moreover, the pharmaceutical industry underestimates the medical need and the potential profitability of antifibrotic drugs. Because the population in developed countries is rapidly aging, IPF is becoming a more common disorder. It is anticipated that companies will begin to look more favorably on drug development in this area as it is becoming apparent that fibrotic diseases as a group may share the same therapeutic targets. In this case, drugs developed for the treatment of pulmonary fibrosis may be useful in the therapy of renal, myocardial, hepatic and other fibrotic diseases as well, broadening the use of such agents.
The complexity of fibrogenesis and the multiplicity of profibrotic and antifibrotic factors, are other reasons for the failure to develop effective drugs. With the advancement of basic research in fibrosis many new targets for drug development have been discovered. However, these discoveries have yet to be translated through to drug discovery and clinical testing. In addition, the consolidation of the pharmaceutical industry has resulted in more focused research programs and less enthusiasm for undertaking higher risk projects that lack “proof of concept”.
There is also a justifiable skepticism about the relevance of the in vitro or animal research methodology that is currently used in drug discovery. The findings of cell culture experiments are not always applicable to the whole organism, and results obtained in mice or rats may not be relevant to humans. Although the bleomycin-induced fibrosis in rodents test tends to identify false positive leads, it might be most relevant in the “therapeutic” rather than the “preventive” protocol. Animal models are often more sensitive than patients in clinical trials, as experimental animals are homogenous in genetic background, sex, age, weight, general health and diet. Compounds which are safe and effective at reasonable doses in a “therapeutic” protocol of bleomycin-induced fibrosis should be considered for optimization and eventual clinical evaluation.
Lack of patentability, toxicity, ignorance of the molecular target or questionable “drugability” of potential antifibrotic drugs are common barriers to their development. In today’s highly competitive environment, few companies are willing to pay for the development of a generic agent like N-acetyl cysteine for the treatment of IPF without proprietary protection. Also, some of the drugs identified as antifibrotics belong to chemical classes known for their toxicity, extensive metabolism, or poor bioavailability and, therefore, are not considered good candidates for development.
It is conceivable that a blockade of only one profibrotic factor cannot stop or reverse fibrogenesis. A drug combination product designed to affect multiple fibrogenic pathways may be required for the effective therapy of IPF.
Another strategy is to search for drugs to enhance resolution of fibrosis. It has been shown that experimental hepatic fibrosis in rodents can be resolved by drugs. The reversibility of pulmonary fibrosis is a controversial subject. It has been suggested that in pulmonary fibrosis the loss of basement membrane, and consequently of normal lung architecture, establishes the point of no return.. Perhaps at earlier stages of the disease pulmonary fibrosis is reversible. Unfortunately, the mechanism of resolution of fibrosis is poorly understood and only a few approaches for the development of fibrolytic targets have been identified.
A better understanding of fibrogenesis and fibrolysis will greatly facilitate discovery and development of new antifibrotic drugs. Based on past experience, many more years are needed to advance the knowledge base of this field to a level adequate for successful design and development of drugs capable to selectively modifying fibrosis in humans. In the interim, available leads should be optimized on the basis of their activity in mice with bleomycin-induced fibrosis or a similar model. If the endpoint of a clinical trial is mortality, the same endpoint should be used in an animal model.
There is also an urgent need for better biomarkers for use in clinical trials. The duration of trials of drugs for treating IPF can be substantially reduced in time and cost if mortality is replaced by an endpoint based on a meaningful biomarker.
The histories of pirfenidone in pulmonary fibrosis reveal several important issues with drug development. The antifibrotic effectiveness of pirfenidone in animals has been known for 14 years and in humans for 10 years. However, resounding proof of its efficacy in human IPF is still not available. This illustrates the imperfect nature of the drug development process and a lack of focus on fibrotic diseases in the pharmaceutical industry.
During the last decade extensive research has been conducted on IPF and therapeutic approaches to treat this condition. New targets for drug development, as well as new leads, were identified. However, there are still no FDA-approved drugs for the treatment of this condition
There have been several barriers to the development of effective therapeutics for IPF. One is the fact that IPF is considered an orphan disease because of its prevalence, lessening the urgency for finding a cure. Moreover, the pharmaceutical industry underestimates the medical need and the potential profitability of antifibrotic drugs. Because the population in developed countries is rapidly aging, IPF is becoming a more common disorder. It is anticipated that companies will begin to look more favorably on drug development in this area as it is becoming apparent that fibrotic diseases as a group may share the same therapeutic targets. In this case, drugs developed for the treatment of pulmonary fibrosis may be useful in the therapy of renal, myocardial, hepatic and other fibrotic diseases as well, broadening the use of such agents.
The complexity of fibrogenesis and the multiplicity of profibrotic and antifibrotic factors, are other reasons for the failure to develop effective drugs. With the advancement of basic research in fibrosis many new targets for drug development have been discovered. However, these discoveries have yet to be translated through to drug discovery and clinical testing. In addition, the consolidation of the pharmaceutical industry has resulted in more focused research programs and less enthusiasm for undertaking higher risk projects that lack “proof of concept”.
There is also a justifiable skepticism about the relevance of the in vitro or animal research methodology that is currently used in drug discovery. The findings of cell culture experiments are not always applicable to the whole organism, and results obtained in mice or rats may not be relevant to humans. Although the bleomycin-induced fibrosis in rodents test tends to identify false positive leads, it might be most relevant in the “therapeutic” rather than the “preventive” protocol. Animal models are often more sensitive than patients in clinical trials, as experimental animals are homogenous in genetic background, sex, age, weight, general health and diet. Compounds which are safe and effective at reasonable doses in a “therapeutic” protocol of bleomycin-induced fibrosis should be considered for optimization and eventual clinical evaluation.
Lack of patentability, toxicity, ignorance of the molecular target or questionable “drugability” of potential antifibrotic drugs are common barriers to their development. In today’s highly competitive environment, few companies are willing to pay for the development of a generic agent like N-acetyl cysteine for the treatment of IPF without proprietary protection. Also, some of the drugs identified as antifibrotics belong to chemical classes known for their toxicity, extensive metabolism, or poor bioavailability and, therefore, are not considered good candidates for development.
It is conceivable that a blockade of only one profibrotic factor cannot stop or reverse fibrogenesis. A drug combination product designed to affect multiple fibrogenic pathways may be required for the effective therapy of IPF.
Another strategy is to search for drugs to enhance resolution of fibrosis. It has been shown that experimental hepatic fibrosis in rodents can be resolved by drugs. The reversibility of pulmonary fibrosis is a controversial subject. It has been suggested that in pulmonary fibrosis the loss of basement membrane, and consequently of normal lung architecture, establishes the point of no return.. Perhaps at earlier stages of the disease pulmonary fibrosis is reversible. Unfortunately, the mechanism of resolution of fibrosis is poorly understood and only a few approaches for the development of fibrolytic targets have been identified.
A better understanding of fibrogenesis and fibrolysis will greatly facilitate discovery and development of new antifibrotic drugs. Based on past experience, many more years are needed to advance the knowledge base of this field to a level adequate for successful design and development of drugs capable to selectively modifying fibrosis in humans. In the interim, available leads should be optimized on the basis of their activity in mice with bleomycin-induced fibrosis or a similar model. If the endpoint of a clinical trial is mortality, the same endpoint should be used in an animal model.
There is also an urgent need for better biomarkers for use in clinical trials. The duration of trials of drugs for treating IPF can be substantially reduced in time and cost if mortality is replaced by an endpoint based on a meaningful biomarker.
The histories of pirfenidone in pulmonary fibrosis reveal several important issues with drug development. The antifibrotic effectiveness of pirfenidone in animals has been known for 14 years and in humans for 10 years. However, resounding proof of its efficacy in human IPF is still not available. This illustrates the imperfect nature of the drug development process and a lack of focus on fibrotic diseases in the pharmaceutical industry.
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