LIVE COVERAGE RECAP: FDA panel says ocriplasmin benefits outweigh risks; recommends approval of ranibizumab

Ocular Surgery News live blogged Thursday's U.S. Food and Drug Administration’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting on ranibizumab and ocriplasmin.

See below for full coverage of the meeting in which the panel voiced its support for Lucentis (ranibizumab, Genentech) and Jetrea (ocriplasmin, ThromboGenics).

4:21 p.m.: Meeting adjourns.

4:19 p.m.: Question 6 - for discussion: If this product is approved, are there any suggestions concerning labeling for this product?

4:17 p.m.: Repka in response to Question 5: There is a modest concern that we are benefiting a portion of people with the drug and not the majority.

4:16 p.m.: Question 5: Do the benefits of administering ocriplasmin for the treatment of vitreomacular adhesion outweigh the potential risks? The panel votes 10 yes, 0 no.

4:14 p.m.: Repka in response to Question 4: I'm concerned that the population that's been exposed to this drug is a relatively healthy population. Additional studies of ocriplasmin are not necessary prior to the drug's approval.

4:11 p.m.: Question 4: Are additional studies needed prior to approval to evaulate the safety of ocriplasmin's effect on the retina? The panel votes 3 yes, 6 no, 1 abstain.

4:09 p.m.: Repka in response to question 3: There was no substantial evidence with regard to the presence of adhesions.

4:07 p.m.: Question 3: Has substantial evidence been provided to demonstrate that ocriplasmin 125 µg is effective for the treatment of all macular holes regardless of the presence of adhesion? The panel votes 1 yes, 8 no, 1 abstain.

4:06 p.m.: Repka in response to Question 2: There is some worry about this as a secondary endpoint, but that the data with a smaller sample is certainly promising.

4:04 p.m.: Question 2: Has substantial evidence been provided to demonstrate that Ocriplasmin 125 µg is effective for the treatment of macular holes associated with vitreomacular adhesions? The panel votes 7 yes, 3 no.

4:02 p.m.: Repka in response to Question 1: There are some concerned that the effect size should be larger.

4:01 p.m.: Question 1: Has substantial evidence been provided to demonstrate that ocriplasmin 125 µg is effective for the treatment of vitreomacular adhesions? The panel votes 10 yes, 0 no.

4 p.m.: Voting ready to begin. The FDA is not required to follow the recommendations of a panel but often does.

3:56 p.m.: Repka: What is the difference in data between macular hole with adhesion and macular hole without adhesion? Answer: There is no data. Ocriplasmin is for patients with VMA, with or without macular hole, not just for the treatment of macular hole.

3:52 p.m.: In regard to potential vision loss, Haller said: "Remember, surgery will leave you with worse vision than ocriplasmin will at 6 months."

3:48 p.m.: Public comment period concludes.

3:47 p.m.: Mark Humayun, MD, PhD, said ocriplasmin offers an option to patients that is safer and has a faster and easier recovery than vitrectomy.

3:44 p.m.: Leonard Feiner, MD, PhD: Encourages panel to consider the difficulties patients must deal with. Having a choice as a physician is valuable.

3:40 p.m.: Maureen Kearney is a patient in a phase 3 study who wanted an option other than vitrectomy. After developing a macular hole, she was treated with ocriplasmin. Within 5 to 10 minutes, she saw flashes of light and eventually was able to read again.

3:36 p.m.: Elias Reichel, MD: "Ocriplasmin, administered in the office setting, could revolutionize how we treat vitreomacular adhesion."

3:34 p.m.: Jeff Todd, COO of Prevent Blindness America: Believes treatment decisions should be left up to the patient, excited about the potential of a retinal treatment that is less invasive. "With this less invasive option [Ocriplasmin], we hope patients will be treated more vigorously for this disease."

3:32 p.m.: Meeting reconvenes. Open Public Hearing Session to begin.

3:18 p.m.: Panel takes 10-minute break. Will resume at 3:30 p.m.

3:17 p.m.: MacDonald: Is it possible to predict who will fair poorly and who will be the one in four who has success? Kaiser: Unfortunately, when we look back at patient data and OCTs, we weren't able to predict if they'd progress to a macular hole. Adhesion release and no release were not able to be predicted.

3:16 p.m.: Visual acuity, VMT progression and VMT progression to macular hole also occurred in placebo patients, not just Ocriplasmin patients.

3:05 p.m.: MacDonald: The sponsor feels that vision loss occurred due to disease progression. Does the FDA not feel that way? Chambers: I just don't have an explanation for the vision loss.

2:57 p.m.: Clarifying question: The VA and quality of life are disappointing. Has the FDA considered elevating that to a primary endpoint instead of a secondary endpoint? If all of these endpoints don't end up to a meaningful change in peoples' lives, what's the point of undergoing the risk of treatment? Answer: There is no validated endpoint for quality of life in ophthalmology.

2:53 p.m.: Panel begins clarifying questions on the FDA presentation.

2:47 p.m.: Chambers: No concern over dropouts, deaths. Not related to the product.

2:35 p.m.: Wiley Chambers, MD, and Jennifer Harris, MD, discuss ocriplasmin for the FDA.

2:31 p.m.: Repka: "Why does the mean change in vision over time look so similar between trajectory and outcome?" Answer: The endpoint is at 6 months. A VA improvement is seen at 3 to 6 months and works its way out in 1 to 2 years. There's also a ceiling effect with the VA that can be achieved.

2:27 p.m.: Clarifying question: Philip Lavin, PhD. "Was the idea of performing vitrectomy standardized within the trial?" Answer: Peter Kaiser, MD, said the surgery was not standardized because it is not an emergency procedure and patients determined if they received the surgery.

2:21 p.m.: Clarifying question: Why does the drug stop working at the surface of the retina? Answer: Ocriplasmin's effects are similar to that of plasmin. It degrades ILM components and causes vitreolysis.

2:16 p.m.: Repka: Is the background that we're looking at in this disease far worse than what we're seeing today, if we're using OCT as our determining vehicle? Haller's answer: Macular hole data is much better.

2:11 p.m.: Clarifying question from Lynn K. Gordon: "If the macular hole patients were separated from the VMA patients, what would that data look like?" Answer: That data is not readily available.

2:02 p.m.: Haller: In conclusion, there are limited treatment options for VMA patients, and ocriplasmin has an unequivocal benefit in one in four patients.

1:59 p.m.: Haller: "Those patients who receive Ocriplasmin have greater benefits than the placebos...The benefits of Ocriplasmin clearly outweigh the risks."

1:55 p.m.: Haller: A single dose of ocriplasmin resolves VMA non-surgically, has a high rate of macular hole closure, improves patient quality of life, decreases the need for vitrectomy.

1:51 p.m.: Julia Haller, MD, discusses the benefits and risks of ocriplasmin for Thrombogenics.

1:50 p.m.: Klepper: Safety conclusions are that the majority of VA decreases were resolved, most AEs were mild to moderate and transient and ocriplasmin was generally well-tolerated.

1:45 p.m.: Klepper: No deaths were related to drug use. All serious adverse events occurred in less than ​1% patients.

1:40 p.m.: Michael J. Klepper, MD, discusses the safety of ocriplasmin.

1:39 p.m.: Brazzell: Ocriplasmin efficacy conclusions include higher rate of VMA resolution, higher rate of total PVD induction and all secondary endpoints were met.

1:37 p.m.: Brazzell: In patients with macular hole at baseline, non-surgical macular hole closure was seen at day 28.

1:34 p.m.: Brazzell: Ocriplasmin achieved the primary endpoint in both Phase 3 trials. VMA resolution was observed as early as day 7.

1:27 p.m.: Brazzell: Seven studies have been performed with ocriplasmin thus far. The two Phase 3 randomized studies included 652 injected eyes, with a 6-month follow up. All patients included had symptomatic VMA with a VA of ≥20/25.

1:26 p.m.: Ocriplasmin uses human plasmin to break down the vitreous, resulting in liquefaction, Brazzell says.

1:25 p.m.: Kim Brazzell, PhD, begins presentation on mechanism of action of ocriplasmin for Thrombogenics.

1:23 p.m.: Watchful waiting is usually employed first, followed by vitrectomy, Kaiser said. During watchful waiting, the condition continues to progress and surgical outcomes could be decreased. Pharmacological treatments decrease these burdens.

1:21 p.m.: Kaiser: Risks of vitrectomy include retinal tear and detachment, hemorrhage, endophthalmitis and a small risk of complete vision loss.

1:18 p.m.: Kaiser: The current management of symptomatic VMA involves only watchful waiting and vitrectomy.

1:17 p.m.: Kaiser: Patients with VMA tend to have a visual acuity of 20/25 and 20/60, unless they have a macular hole in which the VA would be 20/80 to 20/100.

1:14 p.m.: OCT images are used to identify vitreomacular separation and adhesion, Kaiser says.

1:11 p.m.: Kaiser: Ocriplasmin is the first treatment for symptomatic VMA. Two Phase 3 trials were performed, resulting in a statistically significantly high rate of resolution of VMA at 28 days.

1:10 p.m.: Peter Kaiser, MD, discusses the use of ocriplasmin for Thrombogenics.

1:09 p.m.: ThromboGenics, Inc. introduces ocriplasmin, an intravitreal injection for vitreomacular adhesion.

1:07 p.m.: Wiley Chambers, MD, makes introductory remarks.

1:04 p.m.: Yvette Waples, Pharm.D., reads disclaimers.

1:01 p.m.: Michael X. Repka, MD, commences meeting and introduces members of Dermatologic and Ophthalmic Drugs Advisory Committee members for the afternoon session on ocriplasmin.

12:10 p.m.: Panel concludes session considering use of ranibizumab for the proposed indication of diabetic macular edema.

12:08 p.m.: Susan M. MacDonald, MD, calls for both doses to be approved.

12 p.m.: William B. Phillips II, MD, calls for separate packaging for 0.3 mg dose and 0.5 mg dose.

11:59 a.m.: Stephen S. Feman, MD, MPH, FACS, calls for separate labeling according to dose.

11:57 a.m.: Repka favors appropriate labeling per dose.

11:56 a.m.: On question 7, committee votes “yes” 7, “no” 2, and 1 abstaining.

11:55 a.m.: Lynn K. Gordon, MD, asks if lower dose would include labeling on potential death in DME patients.

11:52 a.m.: Chambers asks, one package insert or two package inserts?

11: 50 a.m.: Question 7: Do you have any suggestions concerning the labeling of the product? Discussion ensues regarding individual packaging and separate labeling.

11:45 a.m.: Question 6: Do you recommend for approval the 0.3 mg dose of Lucentis administered monthly for treatment of DME? The panel votes “yes” unanimously 10-0. Repka: “The panel is unanimous in recognizing efficacy and safety of this dose.”

11:40 a.m.: Question 5: Do you recommend for approval the 0.5 mg dose of Lucentis administered monthly for treatment of DME? Committee votes 8 “yes” and 2 “no.” Repka: The panel finds that the dose works well, but the concern is that there may be no need to use more than the 0.3 mg dose.

11:35 a.m.: Question 4: Are additional studies needed prior to approval to evaluate the safety of Lucentis? Committee votes 9 “no,” 0 “yes,” and 1 abstaining. Repka: Prior to approval, no new studies are needed, but there is concern that there should be continued postmarketing surveillance.

11:32 a.m.: Question 3: Has substantial evidence of efficacy been provided to demonstrate that Lucentis is effective for the treatment of diabetic macular edema? The committee unanimously votes “yes,” 10-0.

11:27 a.m.: Question 2: Is there a clinically significant difference in safety between the two doses? Committee votes 4 “yes,” 4 “no,” and 2 abstaining. Repka: The low adverse event rate makes it hard to determine a clinically significant difference between the two doses.

11:24 a.m.: Members comment that they voted “no” because there is no statistically significant difference in efficacy according to data presented by the sponsors.

11:23 a.m.: Question 1: Is there a clinically significant difference in efficacy between 0.3 mg and 0.5 mg doses for treatment of DME? Committee votes “no” unanimously 10-0.

11:22 a.m.: Seven questions are being presented to the committee. The committee will vote on each question.

11:20 a.m.: Questions to the committee begin. The FDA is not required to follow the recommendations of a panel but often does.

11:15 a.m.: Public comment period comes to an end. FDA panel seeks further clarification from Adamis before continuing.

10:59 a.m.: Patricia Corirossi, DME patient and diabetic for 48 years, relates dramatic improvement in her quality of life after treatment with ranibizumab. Several other speakers recount similar success and improved quality of life with ranibizumab treatment.

10:56 a.m.: Victor Gonzales, American Diabetes Association, supports use of ranibizumab for DME.

10:53 a.m.: Helen D. Nickerson, PhD, Juvenile Diabetes Research Foundation: 20% of patients with diabetes have diabetic retinal disease. Laser has proven effective in improving vision but not restoring vision. Ranibizumab would be an effective treatment for DME.

10:48 a.m.: Narinder Sharma, president of AMD Alliance International: Anti-VEGFs have halted blood vessel formation and saved vision in AMD. Efficacy of ranibizumab for DME is similar to efficacy for AMD."We know that it works for DME." 

10:47 a.m.: Michael Elman, DRCR.net, cites "wow factor" of 2-year efficacy data of ranibizumab.

10:41 a.m.: Jeff Todd, COO of Prevent Blindness America, cites dramatic rise in diabetic retinal disease in the last decade and lack of treatments a decade ago. He says now there are more available safe and effective treatment options.

10:37 a.m.: Panel returns from break; public portion of hearing is set to begin.

10:27 a.m.: Panel members and company representatives have been discussing study methodology and timelines. There is a break in the proceedings. Discussion will resume at 10:35 AM.

10:23 a.m.: Wide-ranging discussion continues about study design and execution.

10:16 a.m.: OSN is awaiting conclusions to avoid inconsistent statements about study methodology and timelines.

10:11 a.m.: Clarifying questions: Chambers: After 18 months, there was reverse inflection where data showed a positive trend.

9:58 a.m.: Lloyd: 0.5 mg dose most efficacious in one study, 0.3 mg dose in the other.

9:55 a.m.: Lloyd: 0.3 mg dose statistically significantly more effective than sham.

9:52 a.m.: Lloyd: Analysis of month 36 data was necessary to make a determination of efficacy.

9:41 a.m.: Lloyd: Genentech, FDA met in 2006 to design study for ranibizumab for DME. Clinical trial extended to 3 years. Primary outcome measure was proportion of patients gaining 15 or more letters in Snellen VA. Sham treatment arm patients given a treatment option based on VA. Sham arm became a treatment arm. Ninety percent of patients had nonproliferative diabetic retinopathy.

9:36 a.m.: Lloyd: Discusses approval timeline of ranibizumab (Lucentis, Genentech) and recent approval for treatment of AMD and macular edema secondary to central retinal vein occlusion and branch retinal vein occlusion.

9:35 a.m.: Rhea A. Lloyd, MD, FDA Medical Officer, takes the floor.

9:34 a.m.: FDA proceeds with its presentations.

[NOTE: Blog text from 9:25 to 9:34 a.m. has been updated to clarify attribution.]

9:34 a.m.: Adamis: Ranibizumab takes 9 days to be cleared from systemic circulation.

9:32 a.m.: Adamis cites difficulty of teasing out cardiac risks associated with ranibizumab.

9:30 a.m.: Question about difference in rates of adverse events between doses. Adamis attributes events to injection-related factors.

9:28 a.m.: Susan M. McDonald, MD, asks whether it is feasible to split a 0.5-mg dose, one for each eye when the patient is undergoing bilateral treatment, thus decreasing the dose in each eye and decreasing the cost of treatment. Adamis does not recommend sharing a single-dose bottle.

9:25 a.m.: Adamis cites RIDE/RISE, RESTORE, DRCR, APTC Events studies. The actual number of adverse events is low. There is no consistent signal of risk, but risk is addressed on the label to be thorough and proactive.

9:20 a.m.: FDA panel: Can a larger dose reduce the need for monthly injections? Answer: Short answer is yes; more in the eye allows for longer duration, but greater dose could have other effects.

9:17 a.m.: Panel asks for declaration of minimum effective dose. Answer: 0.3 mg.

9:10 a.m.: FDA panel asks for more specifics on Genentech's ranibizumab studies.

9:07 a.m.: Adamis recommends 0.3 mg dose as optimal.

9:03 a.m.: Adamis: Adverse Events of Special Interest (AESI) is a new methodology has that introduces a broader spectrum of adverse events under study.

9 a.m.: Adamis: Regarding adverse events, myocardial infarction rate was higher with 0.3 mg dose but there was no evidence of dose relationship.

8:57 a.m.: Ehrlich: Ranibizumab improves vision, and provides rapid and sustained improvement for up to 3 years.

8:55 a.m.: Ehrlich: Ranibizumab prevents the development of diabetic retinopathy.

8:53 a.m.: Ehrlich: Rapid and significant improvement in retinal edema was seen by OCT after the first treatment.

8:52 a.m.: Ehrlich: Statistically significant improvements were made in contrast sensitivity in both ranibizumab groups. Average of 11-12 lines of improvement in VA at 2 years was maintained at 3 years.

8:51 a.m.: Ehrlich: Fewer patients with poor VA in ranibizumab groups.

8:49 a.m.: Ehrlich: Snellen visual acuity was statistically significantly improved at 2 years with either dose.

8:47 a.m.: Ehrlich: "The effiacy data of either dose are extremely similar."

8:40 a.m.: Ehrlich discusses RIDE and RISE studies (3-year phase 3 clinical trials randomized to sham, intravitreal injection 0.3 mg ranibizumab or 0.5 mg ranibizumab).

8:39 a.m.: Jason S. Ehrlich, MD, PhD takes the floor.

8:38 a.m.: D'Amico: "Diabetic macular edema ... affects patients in the most productive years of life. ... Diabetic macular edema is an extremely important unmet medical need."

8:37 a.m.: D'Amico: "Surgery can be dispensed with rather quickly."

8:35 a.m.: D'Amico: Laser treatment has been proven to have limited efficacy. Intravitreal triamcinolone, another treatment, poses risk for glaucoma and cataract.

8:33 a.m.: D'Amico: DME the most overlooked complication of diabetic retinopathy. The existing treatments are laser, anti-VEGFs, steroids and vitreal surgery.

8:32 a.m.: D'Amico: OCT is a non-invasive and painless modality for imaging deep ocular structures.

8:31 a.m.: D'Amico: "It's a problem of incompetence or weakness of the retinal vessels."

8:30 a.m.: D'Amico: Burden of disease: Diabetes is the leading cause of blindness in adults older than age 20. World Health Organization statistics attribute diabetic retinopathy as the cause of blindness in 5% of the world’s blind, or 5 million people. Approximately 8.3% of Americans have diabetes.

8:28 a.m.: Adamis introduces Donald J. D'Amico, MD, Weill Cornell Medical College. He is a paid consultant to Genentech and has equity in a laser manufacturing company.

8:25 a.m.: Adamis: Ranibizumab improves vision within 7 days after dosing.

8:24 a.m.: Adamis: Half of ranibizumab cleared from the system within an hour of dosing.

8:21 a.m.: Adamis: Potential efficacy of anti-VEGF established in mid-1990s for the treatment of DME.

8:18 a.m.: Adamis: VEGF discovered in the early 1990s as primary biochemical trigger of blood vessel proliferation in AMD and DME.

8:17 a.m.: Adamis: Proliferative diabetic retinopathy complicates DME and increases risk of vision loss.

8:16 a.m.: Adamis: Laser therapy has been standard of care for diabetic macular edema since 1985.

8:14 a.m.: Adamis: Leaking blood vessels in the retina lead to macular edema in diabetic eyes.

8:12 a.m.: Anthony P. Adamis, MD, VP, Global Head of Ophthalmology, Genentech, begins sponsor presentation.

8:10 a.m.: Dr. Chambers presents plaque recognizing Dr. Repka for his service to the committee.

8:09 a.m.: Dr. Chambers states that the FDA has not made a decision, despite what may have been reported in the media.

8:08 a.m.: Wiley Chambers, MD, makes introductory remarks.

8:06 a.m.: Genentech is applying for a supplement to its biologics license application for ranibizumab (Lucentis) for the treatment of diabetic macular edema.

8:02 a.m.: Food and Drug Administration Center for Drug Evaluation and Research Dermatologic and Ophthalmic Drugs Advisory Committee Chairperson Michael X. Repka, MD, commences meeting and introduces committee members. Yvette Waples, PharmD, reads disclaimers.