RESPONSES TO QUESTIONS FROM WEBINAR ON C3G CLINICAL DEVELOPMENT PROGRAMS IN PHARMA; June 6, 2018
QUESTIONS TO CHEMOCENTRYX
RESPONDENT: Peter Staehr, MD VP, Clinical Development and Translational Medicine, ChemoCentryx
QUESTION: How is avacopan similar/different to the intent/outcome of eculizumab?
RESPONSE: While both avacopan and eculizumab target the overactive alternative pathway of the body’s complement system in the treatment of C3G (please refer to the Chemocentryx slide 9 & 10 for the background and a schematic diagram), the two drugs work at different points of the complement protein synthesis cascade.
Eculizumab is a monoclonal antibody inhibitor of the protein C5, has to be given as an intravenous infusion and cannot be taken by mouth. It inhibits the breakdown of protein C5 into C5a and C5b. C5a, through binding to the receptor C5aR, is involved in the recruitment of inflammatory cells to the kidneys which is one of the causes of kidney damage in C3G. As eculizumab also prevents the generation of C5b (which is needed for the formation of the so-called MAC [Membrane Attack Complex] to fight infections) it has been shown to make a patient more susceptible to meningococcal infection.*
In contrast, avacopan is an oral drug that inhibits the C5a receptor, which consequently may prevent the inflammatory response mediated by C5a. As it only blocks the C5a receptor, avacopan would leave the function of C5a, C5b and MAC intact. Since some patients with C3G have shown improvement with eculizumab, it is hoped that avacopan, while administered by mouth rather than infusion, can produce the desired therapeutic effect without the side effects involved with eculizumab and reduced levels of MAC .
Information from above has been extracted from this review article: Horiuchi,T. et al. Inflammation and Regeneration 2016; 36:11
inflammregen.biomedcentral....
* Refer to FDA index page:
accessdata.fda.gov/scripts/...
QUESTIONS TO ACHILLION
RESPONDENT: •Dr. Hethal Kocinski ; Executive Director of Clinical Development & Head of Clinical Nephrology, Achillion Pharmaceuticals
QUESTION: Can Dr Kocinsky describe any adverse events or side effects observed in the Phase I/II trials so far?
RESPONSE: Achillion Response: More than 150 healthy volunteers and patients have been dosed with ACH-4471 in our studies as of May 2018. During this period, no subjects or patients discontinued ACH-4471 for any side effect or adverse event. We plan to share additional details regarding the safety and efficacy findings from our ongoing Phase 2 clinical trials of ACH-4471 as data becomes available. Achillion shares news and updates regarding the development of ACH-4471 on our website at achillion.com.
QUESTION:ACH4471 is in phase 2 - what's the expected timing for end approval assuming successful trials?
RESPONSE: Achillion Response: As we are in Phase 2 development with ACH-4471, we do not currently have an estimate to share regarding the timing of approval. We recognize the pressing need for new and targeted treatment options for those affected by C3G. Each day we are working with our research partners, regulators, and the patient community around the world to bring a factor D inhibitor to patients as quickly and responsibly as possible. A crucial step in advancing ACH-4471 towards approval is raising awareness and recruiting patients to participate in our global Phase 2 studies assessing the effects of this investigational treatment in those with C3G. We include target dates for the estimated completion of each of our ongoing clinical trials at clinicaltrials.gov. These Phase 2 studies, and the information generated by the participating patients and researchers, will help to inform timing expectations for conducting a Phase 3 clinical trial to support drug approval.
QUESTION:Also, is FDA approval as rigorous given C3G is fairly rare?
RESPONSE: Achillion Response: Patients with rare diseases deserve the same quality, safety and efficacy in their approved treatments as patients with more common diseases. Approval of drugs for both rare and common diseases are based on substantial evidence of efficacy and safety from adequate and well-controlled clinical trials. As there are certain aspects of developing drugs for common diseases that may not be possible for rare diseases, FDA is able to exercise its scientific judgment in determining the type and amount of clinical data that is required for an approval. (1)
QUESTION:If you participate in the phase 2 trial, are you able to participate in phase 3?
RESPONSE: Achillion Response: Achillion plans to offer an extension trial so that investigators may continue to keep patients on ACH-4471 after completion of their Phase 2 trial, as long as the clinical program continues, and until the drug is approved and available commercially. Therefore, Phase 2 patients would not participate in Phase 3 trials.