Biologics in 2016: How Do We Select the Most Appropriate Agent? Gary R. Lichtenstein, MD, FACG University of PA School of Medicine Philadelphia, PA

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1 Biologics in 2016: How Do We Select the Most Appropriate Agent? Gary R. Lichtenstein, MD, FACG University of PA School of Medicine Philadelphia, PA Overview Indications and Drug Selection Contraindications and safety Immunomodulators Optimization Controversies Page 1 of 26

2 Anti-TNF Agents for CD or UC Infliximab Adalimumab Golimumab Certolizumab Pegol VL VH PEG No Fc CH 1 Mouse Human PEG, polyethylene glycol. IgG 1 Chimeric monoclonal antibody (75% human IgG 1 isotype) IgG 1 Human recombinant antibody (100% human IgG 1 isotype) PEG Humanized Fab fragment (95% human IgG 1 isotype) Selective Adhesion Molecules in IBD Natalizumab: Humanized mab to α4β1 Nonselective: Associated with PML Vedolizumab: (MLN-002) Humanized mab to α4β7 - Selective to GI tract Page 2 of 26

3 Overview Indications and drug selection Contraindications and safety Immunomodulators Optimization Controversies Background Anti-TNF antibodies and Anti-Integrin therapies are the most effective approved therapies available to treat IBD Select patients who will benefit: those with active inflammatory disease, ideally before onset of complicated disease behavior Prior to and after initiation of biologic therapy it is important to be aware of safety risks, and attempt to avoid adverse events that are preventable Optimal and more durable response is obtained when combined with an immune modulator Need to select the correct population Lymphoma : Especially < 30 yo and > 50 yo: Male >> Female Therapeutic Drug Monitoring is advantageous Page 3 of 26

4 I. Indications and Drug Selection: Consider the Clinical Scenario Disease: Crohn s disease or ulcerative colitis Age of patient Severity of flare Hospitalized or outpatient? Refractory to conventional therapy which medication(s) were used previously? Fistulizing Crohn s disease Extraintestinal manifestations Post-operative prophylaxis in Crohn s disease? Newly diagnosed? Patient Prognosis Anti TNF: Drug Selection by Indication Infliximab Adalimumab Certolizumab Pegol Golimumab Luminal CD Fistulizing CD Mild to Moderate UC (Outpatient) Moderate to Severe UC (Hospitalized) Pregnancy Extraintestinal manifestations Page 4 of 26

5 Anti-Integrin: Drug Selection by Indication Natalizumab Vedolizumab Luminal CD Fistulizing CD Mild to Moderate UC (Outpatient) Moderate to Severe UC (Hospitalized) Pregnancy Critical Component Presence of Inflammation The key patient selection factor for treatment with Anti-TNF therapy and Anti-Integrin therapy Page 5 of 26

6 SONIC Corticosteroid-Free Clinical Remission at Week 26 in Patients With Crohn s Disease by Baseline Endoscopy Status AZA + placebo (n=170) IFX + placebo (n=169) IFX + AZA (n=169) Proportion of Patients (%) P=0.002 P=0.12 P=0.37 P=0.69 P=0.14 P= /115 P< /99 68/111 Lesions (n=325) P= P= /27 12/36 12/30 6/28 13/34 16/28 No Lesions (n=93) No Endoscopy or UTD (n=90) AZA, azathioprine; IFX, infliximab; UTD, unable to determine Colombel JF et al. N Engl J Med. 2010;362:1383. Biologic Therapy: Contraindications and Safety Infection TB HBV HIV Serious Infections: Abscess, Sepsis, Congestive heart failure Multiple sclerosis/demyelinating disease Lymphoproliferative disorder Other Malignancies? Inability to give informed consent or does not desire biologic Page 6 of 26

7 Anti-TNF Therapy: Risk for Serious Opportunistic Infections Pneumocystosis Histoplasmosis Candidiasis Listeriosis CMV Atypical mycobacteria Aspergillosis Cocidiomycosis Cryptococcus Herpetic Salmonellosis Legionellosis Blastomycosis Other Source: 1.) 2.) 3.) 4.) Minimizing Toxicity for Anti-TNF and Anti-Integrin Therapy Exclude TB prior to initiation (Anti-TNF) CXR, ppd, quantiferon TB gold If immunocompromised, PPD and TB may be negative Exclude the presence of active infection prior to initiation Abscess, C. difficile, CMV Check serology for Hepatitis B Vaccination for age-appropriate disease Influenza, hepatitis A and B, pneumococcal pneumonia, herpes zoster Kane S. Curr Gastroenterol Rep. 2010;12(6): Page 7 of 26

8 Vaccines in IBD Patients Source: General Vaccination Considerations In the IBD Patient Titers to check at first office visit: MMR If vaccination history unknown Varicella If vaccination history or history of chicken pox/zoster unknown Hepatitis A Except those with evidence of protective titer within 5 years of vaccine administration Hepatitis B Except those with evidence of protective titer within 5 years of vaccine administration Vaccinations to administer in specific patient groups regardless of immunosuppressive drug use: Tdap Hepatitis A HPV Hepatitis B Influenza Meningococcal Pneumococcal Vaccinations to consider if NO plans to start immunosuppressive therapy in 4-12 weeks: MMR Varicella Zoster Wasan SK, et al. Am J Gastroenterol. 2010;105(6): DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7: Page 8 of 26

9 Consider Avoidance of AntiTNF Mechanism Prior TB (also Histoplasmosis, Aspergillosis, etc.) Prior Melanoma CHF (NYHA class III, IV) Prior Multiple Sclerosis / Optic Neuritis Prior AntiTNF mediated Pustular Psoriasis Prior Anti-TNF Drug Induced SLE reaction? Prior other malignancies? Prior Anti-TNF primary failure - if TDM done Consider Use of AntiTNF Mechanism over Anti-Integrin Mechanism Severe Fistulizing Crohn s Sever Hospitalized UC /CD need acute onset of action Pregnancy more data that anti-integrin (VEDO is class B) Prior VEDO failure (? With dose escalation to 300 mg iv every 4-6 weeks: since no TDM available) (Note: Dose escalation of VEDO is not an approved dosage) Page 9 of 26

10 Overview Indications and drug selection Contraindications and safety Immunomodulators Optimization Current Medical Therapy Inadequacy Our Current Medical therapy for IBD is effective in some patients. There is a large unmet need for IBD patients with our current medical therapy We are learning how to better use the medications we have and optimize therapy Combination Therapy Gary R. Lichtenstein, MD Therapeutic Professor Drug of Medicine Monitoring Prognostication Director, Center for IBD University of Pennsylvania School of Medicine There still remain Philadelphia, a large PA number of patients that face surgery with IBD; though there has been improvement Continued and future research focusing of disease treatment is needed. Page 10 of 26

11 ACCENT I, CHARM and PRECISE 2 40% 30% 20% 10% 0% 40% 30% 20% 10% 0% Clinical Remission in UC: ACT (Infliximab), ULTRA-2 (Adalimumab) and PURSUIT (Golimumab) Infliximab 8 Weeks ** ** Infliximab 10 mg/kg Infliximab 5 mg/kg Placebo Infliximab 54 Weeks ** ** Infliximab 10 mg/kg Infliximab 5 mg/kg 1 Placebo Patients failing 5-ASA/Steroids/IS 40% 30% 20% 10% 40% 30% 20% 10% 0% 0% Adalimumab 8 Weeks Adalimumab Placebo Adalimumab 52 Weeks Adalimumab Placebo 1.) Rutgeerts P, et al. N Engl J Med. 2005;353: ; 2.) Sandborn WJ, et al. Gastroenterology. 2012;142: ; 3.) Sandborn WJ, et al. Gastroenterology. 2014;146:85-95; 4.) Sandborn WJ, et al. Gastroenterology. 2014;146:96-109; 1 ** * % 30% 20% 10% 0% 40% 30% 20% 10% 0% Golimumab 6 Weeks ** ** Golimumab 400/200 mg Golimumab 100 mg Golimumab 200/100 mg Golimumab 50 mg Placebo Golimumab 54 Weeks ** Placebo * P<.05 versus placebo; ** P<.01 versus placebo 4 Page 11 of 26

12 Approaches Targeting Leukocyte Trafficking A B αlβ2 αmβ2 α4β7 α4β1 αlβ2 αmβ2 α4β7 α4β1 ICAM-2 ICAM-1 MAdCAM-1 VCAM-1 ICAM-2 ICAM-1 MAdCAM-1 VCAM-1 Natalizumab, AJM300 Vedolizumab, AMG 181, Etrolizumab, PF-00547,659 Danese S, et al. Gastroenterology. 2014;147(5): Page 12 of 26

13 Vedolizumab in Crohn s Disease: Clinical Remission at Week 6 and 10 Patients, % P=.05 Clinical Remission at Week Overall population 31.4 Failure Naïve TNF antagonist experience Placebo Patients, % P=.001 Clinical Remission at Week 10 P< Overall population Vedolizumab Q8W 35.3 Failure Naïve TNF antagonist experience Sands BE et al. Gastroenterology. 2014;147: GEMINI I Week 6 Results: Clinical Response and Remission in TNF Failure and TNF-Naïve Patients (Exploratory Endpoints) TNF Failure TNF-Naive (13.7, 39.9)* (3.9, 32.9)* (2.4, 30.2)* (-9.8, 22.8)* *95% CI for difference from placebo. Clinical response was defined as reduction in complete Mayo score of 3 points and 30% from baseline with an accompanying decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore of 1 point. Clinical remission was defined as a complete Mayo score of 2 points and no individual subscore >1 point. Feagan BG, et al. N Engl J Med. 2013;369: Page 13 of 26

14 GEMINI I Week 6 Results: Primary and Secondary Endpoints 100 Placebo, n=149 VDZ, n= P< P= Patients (%) P= Clinical response (Primary endpoint) Clinical remission (Secondary endpoint) Mucosal healing (Secondary endpoint) P values are vs placebo. Feagan BG, et al. N Engl J Med. 2013;369: GEMINI I Week 6 Results: Clinical Response and Remission in TNF Failure and TNF Naïve Patients (Exploratory Endpoints) TNF Failure Placebo, n=63 VDZ, n= TNF Naive Placebo, n=76 VDZ, n=130 (13.7, 39.9)* Patients (%) (3.9, 32.9)* Clinical response (-9.8, 22.8)* Clinical remission Patients (%) Clinical response (2.4, 30.2)* Clinical remission *95% CI for difference from placebo. Feagan BG, et al. N Engl J Med. 2013;369: Page 14 of 26

15 GEMINI I Week 52 Results: Primary and Key Secondary Endpoints 100 Placebo, n=126 VDZ Q8, n=122 VDZ Q4, n=125 Patients (%) P< P< P< P< Clinical remission (Primary endpoint) Mucosal healing (Secondary endpoint) P values are vs placebo. All patients were Week 6 responders Feagan BG, et al. N Engl J Med. 2013;369: Infusion-Related Reactions Infusion-related reactions (IRRs) and hypersensitivity reactions have occurred, including a case of anaphylaxis (1 out of 1434 patients treated with vedolizumab [0.07%]) Allergic reactions including dyspnea, bronochospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed 4% of patients treated with vedolizumab experienced an IRR in GEMINI I and in GEMINI II, versus 3% of patients treated with placebo The most frequently observed IRRs in the patients treated with vedolizumab (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria, and vomiting. Each of these adverse reactions occurred in <1% of all patients treated with vedolizumab and no individual adverse reaction reported occurred at a rate above 1% Less than 1% of patients treated with vedolizumab had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1% Vedolizumab [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May Page 15 of 26

16 Immunogenicity In GEMINI I and GEMINI II, in patients who received vedolizumab, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than 5 half-lives after last dose) During treatment, 56 of 1434 (4%) of patients treated with vedolizumab had detectable anti-vdz antibody at any time during the 52 weeks of continuous treatment Nine of 56 patients were persistently positive (at 2 or more study visits) for anti-vdz antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab Among 8 of these 9 subjects with persistently positive anti-vdz antibody and available vedolizumab concentration data, 6 had undetectable and 2 had reduced vedolizumab concentrations. None of the 9 subjects with persistently positive anti-vdz antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials Vedolizimab [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May IBD: Issues With AZA / 6-MP Take 6-12 weeks to work Side effects Pancreatitis (4%), allergy (2%) Bone marrow suppression (4%) Liver toxicity (9%) Infection (serious infection: 2%) Increased risk of lymphoma Non-melanoma skin cancer Abnormal Pap smears Require frequent labs Complete blood count (CBC), liver function tests (LFTs) Candy S, et al. Gut. 1995;37(5): Pearson DC, et al. Ann Intern Med. 1995;123(2): Kotlyar D, et al, Clinical Gastroenterology and Hepatology 2015;13: Page 16 of 26

17 Maintenance of Remission with Azathioprine in Crohn s Disease Patients (%) P = NS 73 Azathioprine (n = 33) Placebo (n = 33) P = Week 12 CDAI < 150 Month 15 CDAI < 175 Candy S et al. Gut. 1995;37: Early AZA Alone Is Ineffective in CD Rate of Trimesters in Remission per Patient During First 3 y, % P = NS Sustained Steroid-Free Clinical Remission to Wk 76, % of Patients P = NS (n = 65) (n = 67) (n = 68) (n = 63) Abbreviation: Tx, transplantation. Left-side graph: Cosnes J, et al. Gastroenterology. 2013;145(4): Right-side graph: Panés J, et al. Gastroenterology. 2013;145(4): Page 17 of 26

18 Risk of Lymphoma with AZA / 6-MP Use 18 studies (among 4383 citations) met inclusion criteria. The SIR for lymphoma was Overall (95% CI, ), 2.80 (95% CI, ) in 8 population studies 9.24 (95% CI, ) in 10 referral studies. Population studies demonstrated an Increased risk among current users (SIR=5.71; 95% CI, ) but No increased risk in former users (SIR=1.42; 95% CI, ). Kotlyar D, et al, Clinical Gastroenterology and Hepatology 2015;13: Risk of Lymphoma with AZA / 6-MP Use Risk Became Significant after One year of exposure Sex* Men have a greater risk than women (RR = 1.98; P <.05) Both sexes were at increased risk for lymphoma Men: SIR for men = 4.50 ( 95% CI ) Women: SIR for women = 2.29 (95% CI ) Age Age 30-59: 1 lymphoma per 2000 pt-yrs of followup Patients < 30 years had the highest RR o SIR=6.99 (CI, 95% CI, ) o Younger men had the highest risk: Men < 30 : SIR~ 9 The absolute risk was highest in patients > 50 years 1:354 cases per patient year RR=4.78 *- subanalysis of 2 studies Kotlyar D, et al, Clinical Gastroenterology and Hepatology 2015;13: Page 18 of 26

19 Steroid Sparing and Toxicity of MTX in Active CD % P =.025 Placebo (n = 47) MTX 25 mg/wk IM (n = 94) % Patients % 17% P = % Able to Discontinue Steroids Unable to Tolerate Medication Feagan BG et al. N Engl J Med. 1995;332:292. Maintenance of Remission with Methotrexate in Crohn s Disease 100 Patients in remission (%) P =.04 Methotrexate Placebo Week Feagan BG et al. N Engl J Med. 2000;342: Page 19 of 26

20 Issues With MTX Often used intramuscularly in Crohn s Disease 1 Common side effects: 1 Nausea/vomiting Bone marrow suppression Scarring of the liver Liver biopsy is needed before and during MTX therapy in certain patients 1 Requires continuous monitoring of CBC and LFTs 2 Contraindicated if attempting pregnancy 2 Category X 1. Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2): Methotrexate injection USP [package insert]. Lake Forest, IL: Hospira, Inc.; Overview Indications and drug selection Contraindications and safety Immunomodulators Optimization Page 20 of 26

21 Defining anti-tnf failure: Secondary Non-response (Loss of Response) Pseudo-failure for symptoms unrelated to active inflammation Pharmacokinetic Inadequate drug levels because of anti-drug antibody Inadequate drug levels because of rapid drug clearance for other reasons Inadequate dose Pharmacodynamic Evolution of resistance to anti-tnf mechanism Dose-limiting adverse event Optimal Therapy with Anti-TNFs: Maximizing Efficacy and Avoiding Loss of Response Give a loading dose Infliximab 5 mg/kg IV at weeks 0, 2 and 6 Adalimumab 160 mg, 80 mg, 40 mg SC EOW Certolizumab pegol 400 mg SC EOW x3 Golimumab 200 mg sq at 0 then 100 mg at 2 wks Give in combination with an immune modulator (mercaptopurine, azathioprine, or methotrexate) If not given in combination with immune modulator, consider infliximab with hydrocortisone pretreatment Avoid episodic dosing Consider smoking cessation Dose optimize early to avoid unintentional episodic dosing? Page 21 of 26

22 Why Give Concomitant Therapy? Lower rates of infusion reactions (best defined with infliximab) Lower rates of anti-drug antibody formation Higher drug levels (independent of effect on antibody formation) Independent effect of a 2 nd active agent Lower rate of loss of response No signal for increased risk of infection (SONIC) Concomitant Treatment with AZA and IFX is Associated with Higher Serum IFX Levels in SONIC Median serum infliximab trough concentrations at Week 46 Median serum infliximab trough concentration* at Week 46 (µg/ml) IFX (n=73) p< IFX/AZA (n=76) *infliximab- or infliximab/azathioprine-treated patients who had serum samples collected prior to infusion at Week 46 (N=149) Colombel JF, et al. New Engl J Med 2010;362: Page 22 of 26

23 UC SUCCESS: Combination Therapy in UC Primary Endpoint: Steroid-Free Remission at Week 16 P=0.017 Percent of Patients (%) P=0.813 P=0.032 n=18 n=17 n=31 Panaccione R, et al. Gastroenterology 2014; 146(2): Assessing Loss of Response Confirmed Active Inflammation Subtherapeutic concentration and positive ADA Therapeutic drug concentration or detectable trough level Subtherapeutic concentration or undetectable trough level Change to another anti-tnf agent If persistent disease Change to treatment with different MOA (non-anti-tnf agent) or Increase dose frequency Consider adding immunosuppressant (if monotherapy) ADA, anti-drug antibodies. Afif W et al. Am J Gastroenterol. 2010;105: Page 23 of 26

24 Treating IBD Beyond Symptoms: Rationale for a Clear Management Strategy Personalized management for IBD will depend on Disease severity at presentation Clinical and biologic prognostic factors Achievement of clinical and biologic remission Maintenance of clinical and biologic remission Patient adherence Therapeutic monitoring Pharmacoeconomics 47 AGA Clinical Pathway for Crohn s Disease: Characterizing Risk Low Risk High Risk >30 years Age at diagnosis <30 years Limited Anatomic involvement Extensive No Perianal and/or severe rectal disease Superficial Ulcers Deep No Prior surgical resection Yes Yes No Stricturing and/or penetrating behavior Yes Sandborn WJ. Gastroenterology. 2014;147: Page 24 of 26

25 AGA Clinical Pathway for Crohn s Disease: Initial Treatment Low-risk patient Ileum and/or proximal colon, none to minimal symptoms Options Budesonide 9 mg/day with or without AZA Tapering course of prednisone with or without AZA Diffuse or left colon, none to minimal symptoms Options Tapering course of prednisone with or without AZA Moderate/high-risk patient Options Anti-TNF monotherapy over no therapy or thiopurine monotherapy Anti-TNF + thiopurine over thiopurine monotherapy or anti-tnf monotherapy Methotrexate for patients who do not tolerate purine analog in combination with anti-tnf Sandborn WJ. Gastroenterology. 2014;147: Is A Treat-to-Target Approach Feasible in IBD? Symptoms QoL Labs CRP Calprotectin? Mucosal healing Hospitalizations Surgery Biologic (Deep remission) Histologic remission Disease modification 50 Page 25 of 26

26 Conclusions Document active inflammation before initiating anti-tnf or anti-integrin Therapy Always consider combination therapy Avoid episodic dosing Treat active infection before starting anti-tnf or anti-integrin Therapy Prevent preventable infections with vaccination Optimize therapy Prognosticate to use appropriate therapy Use biologic (Anti-TNF / Anti-Integrin) therapy in appropriate patient populations and avoid use in specific populations when inappropriate. Page 26 of 26